KR20180042748A - Novel Staphylococcus specific bacteriophage SA7 and antibacterial composition comprising the same - Google Patents

Novel Staphylococcus specific bacteriophage SA7 and antibacterial composition comprising the same Download PDF

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KR20180042748A
KR20180042748A KR1020160135293A KR20160135293A KR20180042748A KR 20180042748 A KR20180042748 A KR 20180042748A KR 1020160135293 A KR1020160135293 A KR 1020160135293A KR 20160135293 A KR20160135293 A KR 20160135293A KR 20180042748 A KR20180042748 A KR 20180042748A
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staphylococcus aureus
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김영주
연영은
이종석
한범구
김현일
박철세
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Abstract

The present invention relates to novel bacteriophage SA7 having destruction capability specific to harmful bacteria, staphylococcus in particular, a pharmacological composition, an antibacterial composition, a feed additive composition, feed, an antiseptic, or a cleaner for preventing or treating infectious disease from staphylococcus which comprises the bacteriophage, and a method for preventing or treating infectious disease from staphylococcus which comprises a step of injecting the bacteriophage to a living organism. The method for preventing or treating infectious disease from staphylococcus by using bacteriophage SA7 has high specificity to staphylococcus compared to chemical materials such as an existing antibiotic agent. The bacteriophage SA7 infects staphylococcus, proliferates in the staphylococcus, and thus has excellent bacteriolysis activity and is highly resistant to physical and chemical stimulation. In addition, hosts such as humans, animals, and plants other than bacteria are not infected by the bacteriophage SA7. Therefore, the bacteriophage SA7 can solve a problem of bacteria resistant to antibiotic agents caused by abuse of antibiotics, a problem of antibiotic agents remaining in food, and a problem of a wide host range. In particular, the bacteriophage SA7 can proliferate in Staphylococcus aureus which is sometimes resistant to antibiotic agents and thus has an advantage of exhibiting an excellent antibacterial effect. Accordingly, the bacteriophage SA7 can be used for various fields in the prevention or treatment of infectious disease from staphylococcus, an antibiotic composition, a feed additive composition, feed, an antiseptic, or a cleaner.

Description

신규한 포도상구균 특이 박테리오파지 SA7 및 이를 포함하는 항균 조성물{Novel Staphylococcus specific bacteriophage SA7 and antibacterial composition comprising the same}Novel staphylococcal-specific bacteriophage SA7 and an antimicrobial composition comprising the novel staphylococcal-specific bacteriophage SA7 and antibacterial composition,

본 발명은 유해세균, 특히 포도상구균에 특이적인 사멸능을 갖는 신규 박테리오파지 SA7, 상기 박테리오파지를 포함하는 포도상구균에 의한 감염성 질병의 예방 또는 치료용 약학적 조성물, 항생용 조성물, 사료 첨가용 조성물, 사료, 소독제 또는 세척제 및 상기 박테리오파지를 개체에 투여하는 단계를 포함하는 포도상구균에 대한 감염성 질병의 예방 또는 치료 방법에 관한 것이다. The present invention relates to a novel bacteriophage SA7 having noxious activity specific to noxious bacteria, particularly staphylococci, a pharmaceutical composition for preventing or treating infectious diseases caused by Staphylococcus aureus including the bacteriophage, an antibiotic composition, , A disinfectant or detergent, and a method of preventing or treating an infectious disease against staphylococci comprising administering the bacteriophage to a subject.

포도상구균은 50% 이상의 건강한 사람, 동물의 피부, 비강 등에서 흔히 발견되며 여드름, 농가진 같은 경증의 피부감염증부터 폐렴, 수막염, 패혈증과 같은 생명을 위협하는 질환들에 이르기까지 다양한 질병을 초래할 수 있다. 또한, 원내감염의 가장 흔한 5가지의 원인 중 하나이며, 종종 수술 후 상처 감염증을 초래한다. 미국 병원에서 매년 약 50만 명의 환자들이 포도상구균 감염증에 걸리는 것으로 알려졌다.Staphylococci are commonly found in more than 50% of healthy people, animal skin, nasal passages, and can lead to a variety of diseases ranging from mild skin infections such as acne and impetigo to life-threatening diseases such as pneumonia, meningitis and sepsis. It is also one of the 5 most common causes of hospital infection and often results in wound infection after surgery. Approximately 500,000 patients in the US hospital each year are known to have staphylococcal infections.

특히, 자연계에 널리 분포되어 있는 황색포도상구균(Staphylococcus aureus; S. aureus)은 세계적으로 널리 알려진 식중독균 중의 하나로, 황금색 색소를 생성하고 용혈성을 가지며 응고효소(coagulase)를 생성하는 종으로, 화농성 질환이나 창상감염 등의 피부감염, 골관절염, 폐렴, 패혈증 등을 일으키는 병원성 높은 대표적인 유해세균으로 알려져 있다(Kim SK et al., The Journal of the Korean Society for Microbiology, 28:251, 1993). Staphylococcus aureus ( S. aureus ), which is widely distributed in nature, is one of the most widely known food poisoning bacteria in the world. It produces golden pigment, has hemolytic activity and produces coagulase. (Kim SK et al., The Journal of the Korean Society for Microbiology, 28: 251, 1993), which is known to be highly pathogenic, causing skin infections such as wound infection, osteoarthritis, pneumonia and sepsis.

황색포도상구균은 일반적으로 환경에 대한 저항성이 강하여 건강한 성인의 비강, 피부, 구강 등에서도 존재하고 동물의 상처부위를 통한 전염이나 식품의 생산과정, 제조 공정 등의 여러 단계를 거치면서 식품 유통망을 타고 짧은 시간에 전국적으로 전파될 수 있으며, 전파된 황색포도상구균은 사람에게 전이되어 또 다른 매개체가 될 수 있다. 따라서 황색포도상구균과 같은 유해세균을 억제하기 위하여 사람과 동물의 질병 치료와 예방에 항생제를 사용하고 있으나, 황색포도상구균에 의한 식중독 발생률은 노로 바이러스와 살모넬라, 병원성 대장균과 함께 꾸준히 높은 수치를 나타내고 있으며 매년 발생이 증가되고 있다(Lee JH et al., Korean Journal for Food Science of Animal Resources,30:410, 2010).Staphylococcus aureus is generally resistant to the environment and is present in nasal passages, skin, oral cavity, etc. of healthy adults. It can also be used in food distribution networks through various steps such as transmission through wound areas of an animal, It can spread nationwide in a short time, and the spread of Staphylococcus aureus can be transferred to humans and become another mediator. Therefore, antibiotics are used for the treatment and prevention of diseases of humans and animals in order to suppress harmful bacteria such as Staphylococcus aureus. However, the incidence of food poisoning due to Staphylococcus aureus has been consistently high with Norovirus, Salmonella and Pathogenic Escherichia coli (Lee, JH et al., Korean Journal of Food Science and Animal Resources, 30: 410, 2010).

또한, 항생제 내성 포도상구균인 메티실린 내성 황색포도상구균(methicillin-resistant Staphylococcus aureus, MRSA)은 주로 병원 내에서의 항생제 남용에 의해 초래된다. 하지만, 오늘날 돼지 등의 동물들이 사육되는 조건이 MRSA 역학의 양자 이동(quantum shift)을 초래하여 지역사회획득 MRSA(community acquired MRSA)의 병원소가 되어왔다. 2010년 항생제 내성에 관한 집담회(Conference on Antimicrobial Resistance)에서 농장 근로자의 MRSA 감염률이 일반 대중 감염률의 760배에 이르는 20-25%로 발표되었다. 이들 직종의 근로자들에 의한 항생제 사용증가는 항생제 내성 균주를 급속히 증가시켜 심각한 문제를 초래할 수도 있다고 보고되고 있다. In addition, methicillin-resistant Staphylococcus aureus (MRSA), an antibiotic-resistant Staphylococcus , is mainly caused by antibiotic abuse within the hospital. Today, however, the conditions under which pigs and other animals are raised have been the hallmarks of community acquired MRSA, resulting in quantum shifts in MRSA dynamics. In the Conference on Antimicrobial Resistance in 2010, the rate of MRSA infection among farm workers was reported to be 20 to 25%, which is 760 times that of the general public infection rate. Increased use of antibiotics by workers in these occupations has been reported to cause serious problems by rapidly increasing antibiotic resistant strains.

한편, 박테리오파지(bacteriophage)는 특정 세균을 감염시켜 감염된 세균의 성장을 억제하고 저해하는 세균 특이적 바이러스를 의미한다. 박테리오파지는 박테리아에 감염(infection)한 후 박테리아 세포 내부에서 증식을 하고, 증식 후 자손 박테리오파지들이 박테리아 밖으로 나올 때 숙주인 박테리아의 세포벽을 파괴하는 방식으로 박테리아를 사멸시키는 능력을 갖고 있다. 박테리오파지의 박테리아 감염 방식은 매우 특이성이 높아서 특정 박테리아에 감염할 수 있는 박테리오파지의 종류는 일부로 한정된다. 즉, 특정 박테리오파지는 특정 범주의 박테리아에만 감염할 수 있고 이로 인하여 특정 박테리오파지는 특정 박테리아만을 사멸시키며 다른 박테리아에는 영향을 주지 않는다. 따라서 최근 세균성 질환의 대처 방안으로 박테리오파지(bacteriophage)의 활용이 크게 주목을 받고 있다. 자연 친화적 방식의 선호로 인하여 박테리오파지에 대한 관심은 어느 때보다 높다고 할 수 있다. 특히 2000년 이후에 항생제 내성균의 증가로 인하여 기존 항생제의 한계성이 나타나고, 기존 항생제의 대체 물질로의 개발 가능성이 부각되면서 다시 박테리오파지가 항-박테리아제로 주목을 받고 있다.On the other hand, bacteriophage refers to a bacterium-specific virus that infects a specific bacterium to inhibit and inhibit the growth of the infected bacterium. Bacteriophages have the ability to kill bacteria by infecting bacteria, multiplying inside bacterial cells, and destroying the cell walls of the host bacteria when the progeny bacteriophages come out of the bacteria after proliferation. The bacteriophage infection method of bacteriophage is highly specific, so the type of bacteriophage that can infect a specific bacterium is limited to some. That is, certain bacteriophages can infect only a specific category of bacteria, which causes certain bacteriophages to kill only certain bacteria and not other bacteria. Recently, the use of bacteriophage has attracted much attention as a countermeasure against bacterial diseases. Interest in bacteriophages is higher than ever because of the preference of nature-friendly methods. Especially, since 2000, the limit of existing antibiotics has appeared due to the increase of antibiotic resistant bacteria, and bacteriophage is attracting attention as an anti - bacterial agent again with the possibility of development as a substitute for existing antibiotics.

그러나, 가축류를 포함하는 개체의 사육에 있어서 중요한 문제가 되고 있는 포도상구균에 의한 감염증을 예방 또는 치료하기 위한 신규한 박테리오파지에 대한 연구는 여전히 부족한 실정이다. 따라서 포도상구균에 특이적인 용균활성을 갖는 박테리오파지 및 이의 응용에 대한 기술 개발이 필요하다. However, research on novel bacteriophages for preventing or treating infectious diseases caused by Staphylococci, which is an important problem in breeding of animals including livestock, is still in short supply. Therefore, it is necessary to develop technology for bacteriophage having lytic activity specific to staphylococci and its application.

KR특허등록번호 10-1432872KR Patent Registration No. 10-1432872

이에 본 발명자들은 포도상구균에 특이적인 용균활성을 갖는 박테리오파지를 분리하고 분리된 박테리오파지의 형태적 및 유전적 특성을 분석하여 상기 박테리오파지가 포도상구균을 선택적으로 사멸시킬 수 있음을 확인함으로써 본 발명을 완성하였다.Accordingly, the present inventors have completed the present invention by separating bacteriophages having lytic activity specific to Staphylococci and analyzing the morphological and genetic characteristics of the separated bacteriophages to confirm that the bacteriophages can selectively kill Staphylococci .

본 발명의 목적은 포도상구균에 특이적인 사멸능을 갖는, 서열번호 1로 표시되는 염기서열로 이루어진 박테리오파지 SA7을 제공하는 것이다.An object of the present invention is to provide a bacteriophage SA7 comprising the nucleotide sequence shown in SEQ ID NO: 1, which has a killing activity specific to Staphylococcus aureus.

본 발명의 또 다른 목적은 상기 박테리오파지 SA7을 포함하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating infectious diseases caused by Staphylococcus aureus comprising the bacteriophage SA7.

본 발명의 또 다른 목적은 상기 박테리오파지 SA7을 포함하는, 항생용 조성물, 사료 첨가용 조성물, 사료, 소독제 또는 세척제를 제공하는 것이다.Yet another object of the present invention is to provide an antibiotic composition, a composition for feed addition, a feed, a disinfectant, or a detergent comprising the bacteriophage SA7.

본 발명의 또 다른 목적은 상기 박테리오파지 SA7을 개체에 투여하는 단계를 포함하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료 방법을 제공하는 것이다.It is still another object of the present invention to provide a method for preventing or treating an infectious disease caused by Staphylococcus, comprising the step of administering the bacteriophage SA7 to an individual.

상기 목적을 달성하기 위하여, 본 발명은 포도상구균에 특이적인 사멸능을 갖는, 서열번호 1로 표시되는 염기서열로 이루어진 박테리오파지 SA7을 제공한다.In order to accomplish the above object, the present invention provides a bacteriophage SA7 comprising the nucleotide sequence shown in SEQ ID NO: 1, which has a killing activity specific to Staphylococcus aureus.

또한, 본 발명은 상기 박테리오파지 SA7을 포함하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating an infectious disease caused by Staphylococcus aureus comprising the bacteriophage SA7.

또한, 본 발명은 상기 박테리오파지 SA7을 포함하는, 항생용 조성물을 제공한다.The present invention also provides an antibiotic composition comprising the bacteriophage SA7.

또한, 본 발명은 상기 박테리오파지 SA7을 포함하는, 사료 첨가용 조성물을 제공한다.In addition, the present invention provides a composition for feed addition comprising the bacteriophage SA7.

또한, 본 발명은 상기 박테리오파지 SA7을 포함하는, 소독제를 제공한다.The present invention also provides a disinfectant comprising the bacteriophage SA7.

또한, 본 발명은 상기 박테리오파지 SA7을 포함하는, 세척제를 제공한다.The present invention also provides a detergent comprising the bacteriophage SA7.

또한, 본 발명은 상기 박테리오파지 SA7을 개체에 투여하는 단계를 포함하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료 방법을 제공한다.The present invention also provides a method for preventing or treating an infectious disease caused by staphylococci, comprising the step of administering the bacteriophage SA7 to an individual.

본 발명의 박테리오파지 SA7을 이용한 포도상구균에 의한 감염성 질병의 예방 또는 치료 방법은 기존의 항생제 등의 화학물질에 비해 포도상구균에 대한 특이성이 매우 높고, 상기 박테리오파지 SA7은 포도상구균에 감염하여 포도상구균 내에서 증식함으로써 용균 활성이 우수하고 물리화학적 자극에 강하다는 장점을 가지고 있다. 또한 본 발명의 박테리오파지 SA7은 사람, 동물, 식물 등 세균 외의 다른 숙주에는 감염되지 않으므로, 항생제의 오남용으로 인한 항생제 내성균의 문제점, 식품 내의 항생제의 잔류 문제, 광범위한 숙주범위의 문제점을 해결할 수 있는 장점이 있다. 특히 본 발명의 박테리오파지 SA7은 항생제 내성 황색포도상구균 내에서도 증식하여 우수한 항균효과를 나타낼 수 있는 이점이 있다. 따라서, 본 발명의 박테리오파지 SA7은 포도상구균에 의한 감염성 질병의 예방 또는 치료, 항생용 조성물, 사료 첨가용 조성물, 사료, 소독제, 또는 세척제 분야에서 다양하게 사용될 수 있다.The method for preventing or treating infectious diseases caused by Staphylococcus aureus using the bacteriophage SA7 of the present invention is highly specific to Staphylococcus aureus as compared with chemicals such as existing antibiotics and the bacteriophage SA7 is infected with Staphylococcus aureus, It has an advantage that it is excellent in lytic activity and strong against physicochemical stimulation by proliferation. In addition, the bacteriophage SA7 of the present invention is not infected by any host other than bacteria such as humans, animals and plants, and thus has an advantage of being able to solve problems of antibiotic resistant bacteria caused by misuse of antibiotics, residual antibiotics in food, have. In particular, the bacteriophage SA7 of the present invention has an advantage that it can proliferate even in antibiotic-resistant Staphylococcus aureus and exhibit an excellent antimicrobial effect. Therefore, the bacteriophage SA7 of the present invention can be used variously in the field of prevention or treatment of infectious diseases caused by staphylococci, compositions for antibiosis, composition for feed addition, feed, disinfectant, or detergent.

도 1은 박테리오파지 SA7의 포도상구균에 대한 용균반 형성 활성을 확인한 결과를 나타낸 도이다.
도 2는 전자 현미경을 통해 박테리오파지 SA7의 형태학적 특성을 확인한 결과를 나타낸 도이다.
도 3은 박테리오파지 SA7의 단백질 패턴을 SDS-PAGE를 통해 확인한 결과를 나타낸 도이다.
도 4는 박테리오파지 SA7의 pH 안정성을 확인한 결과를 나타낸 도이다.
도 5는 박테리오파지 SA7의 열 안정성을 확인한 결과를 나타낸 도이다.Brief Description of the Drawings Fig. 1 is a graph showing the results of confirming the activity of the bacteriophage SA7 for staphylococci formation.
FIG. 2 is a diagram showing the result of confirming the morphological characteristics of bacteriophage SA7 through an electron microscope.
Fig. 3 is a diagram showing the result of SDS-PAGE of the protein pattern of bacteriophage SA7.
4 is a graph showing the result of confirming the pH stability of bacteriophage SA7.
5 is a graph showing the result of checking the thermal stability of bacteriophage SA7.

이하, 본 발명에 대해 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명은 포도상구균에 특이적인 사멸능을 갖는, 서열번호 1로 표시되는 염기서열로 이루어진 박테리오파지 SA7를 제공한다.The present invention provides a bacteriophage SA7 comprising the nucleotide sequence shown in SEQ ID NO: 1, which has a killing activity specific to Staphylococcus aureus.

본 발명에서, 용어 박테리오파지(bacteriophage)는 특정 세균에 감염하여 해당 세균의 성장을 억제하고 저해하는 세균 특이적 바이러스로, 단일 혹은 이중 사슬의 DNA 또는 RNA를 유전 물질로 포함하는 바이러스를 의미한다.In the present invention, the term bacteriophage refers to a bacterium-specific virus that infects a specific bacterium and inhibits and inhibits growth of the bacterium, and includes a single or double-stranded DNA or RNA as a genetic material.

본 발명의 박테리오파지 SA7은 포도상구균 특히, 황색포도상구균에 대해 용균활성이 탁월하나, 살모넬라균, 대장균 및 엔테로코커스속 균주 등의 다른 속 균주에 대해서는 용균활성을 나타내지 않는다. 상기 박테리오파지 SA7은 100-150 nm의 크기로, 정이십면체의 머리를 가지며 수축성 꼬리가 있는 형태인 마이오비리데(Myoviridae)형 박테리오파지에 속하며, 단백질 패턴 분석 결과 110 kDa, 50 kDa, 40 kDa, 32 kDa, 30 kDa의 단백질을 포함하고, 전체 염기서열 분석 결과 34,730 bp의 크기를 갖고 GC함량이 34%, 전체 ORFs의 수는 52개임을 확인하였으며 그 전체 염기서열을 서열번호 1로 표시하였다. 또한 상기 박테리오파지 SA7은 열 및 pH에 대한 안정성이 우수한 특성을 가지고 있다.The bacteriophage SA7 of the present invention is excellent in lytic activity for Staphylococcus, especially Staphylococcus aureus, but does not exhibit lytic activity for other strains such as Salmonella, Escherichia coli and Enterococcus. The bacteriophage SA7 belongs to the Myoviridae type bacteriophage having a size of 100-150 nm and having a regular twenty-sided head and a shrinkable tail, and the protein pattern analysis revealed that the bacteriophage SA7 has a karyotype of 110 kDa, 50 kDa, 40 kDa, 32 kDa and 30 kDa. The total nucleotide sequence analysis showed 34,730 bp. The GC content was 34% and the total number of ORFs was 52. The entire nucleotide sequence thereof was shown in SEQ ID NO: 1. The bacteriophage SA7 has excellent stability against heat and pH.

본 발명의 박테리오파지 SA7은 서열번호 1로 표시되는 염기서열을 전체 유전자의 전체 또는 일부로서 포함할 수 있다. 또한, 본 발명의 박테리오파지 SA7은 서열번호 1로 표시되는 염기서열, 및 상기 염기서열의 기능적 동등물로 이루어질 수 있다. 상기 기능적 동등물이란 염기서열의 변형, 치환의 결과, 상기 서열번호 1로 표시되는 염기서열과 적어도 70% 이상, 바람직하게는 80% 이상, 더욱 바람직하게는 90% 이상, 더더욱 바람직하게는 95% 이상의 서열 상동성을 갖는 것으로, 서열번호 1로 표시되는 염기서열과 실질적으로 동질의 생리활성을 나타내는 서열을 의미한다.The bacteriophage SA7 of the present invention may include the nucleotide sequence shown in SEQ ID NO: 1 as whole or part of the entire gene. In addition, the bacteriophage SA7 of the present invention may comprise the nucleotide sequence shown in SEQ ID NO: 1 and the functional equivalent of the nucleotide sequence. The functional equivalent means at least 70% or more, preferably 80% or more, more preferably 90% or more, still more preferably 95% or more of the nucleotide sequence shown in SEQ ID NO: 1 as a result of modification or substitution of the nucleotide sequence. Or more and having substantially the same physiological activity as the nucleotide sequence shown in SEQ ID NO: 1.

상기와 같은 포도상구균 특이적 용균활성, 내산성, 내염기성 및 내열성은 본 발명의 박테리오파지 SA7을 포도상구균에 의한 감염성 질병의 예방 및 치료용 조성물, 및 상기 박테리오파지 SA7을 유효성분으로 포함하는 다양한 제품에 적용함에 있어, 다양한 온도 및 pH 범위에서의 적용이 가능하게 한다.The bacteriophage SA7 of the present invention can be applied to a composition for the prevention and treatment of infectious diseases caused by staphylococci, and a variety of products containing the bacteriophage SA7 as an active ingredient, such as staphylococcal-specific lytic activity, acid resistance, basic basicity and heat resistance Making it possible to apply it in various temperature and pH ranges.

본 발명의 박테리오파지 SA7은 도축장, 도계장 및 농장 부근의 하수로부터 시료를 채취하여 분리한 박테리오파지로서, 본 발명자들은 이를 박테리오파지 SA7으로 명명하고 2016년 7월 22일 한국미생물보존센터에 수탁번호 KFCC11673P로 기탁하였다. The bacteriophage SA7 of the present invention is a bacteriophage obtained by collecting samples from sewage slaughterhouse, slaughterhouse, and farm, and named it bacteriophage SA7, and deposited it with the deposit number KFCC11673P on July 22, .

또한, 본 발명은 상기 박테리오파지 SA7을 포함하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating an infectious disease caused by Staphylococcus aureus comprising the bacteriophage SA7.

본 발명의 박테리오파지 SA7은 포도상구균에 특이적인 사멸능을 가지므로, 포도상구균에 의한 감염성 질병의 예방 또는 치료용 약학적 조성물에 사용될 수 있다. 상기 포도상구균은 황색포도상구균(Staphylococcus aureus)인 것이 바람직하다.The bacteriophage SA7 of the present invention has an apoptotic activity specific to staphylococci, and thus can be used in pharmaceutical compositions for the prevention or treatment of infectious diseases caused by staphylococci. The staphylococcus is preferably Staphylococcus aureus .

본 발명에 있어서, 상기 "황색포도상구균"은 세포덩어리를 형성하는 그람양성의 통성혐기성 세균이다. 황색포도상구균은 식세포를 죽이는 독소 등을 분비하여 화농성 감염증을 일으키고, 내열성인 외독소를 생산하여 식중독을 일으키는 균으로 살모넬라균 및 장염비브리오균 다음으로 식중독을 많이 일으키는 균이다.In the present invention, the "Staphylococcus aureus" is a gram-positive tuberous anaerobic bacterium that forms a cell mass. Staphylococcus aureus is a bacterium that causes food poisoning by producing salmonella and enteritis Vibrio germs, which cause a food poisoning by producing toxic toxins such as toxins that kill phagocytes and cause pyogenic infections.

본 발명에 있어서, 상기 황색포도상구균은 항생제 내성 황색포도상구균일 수 있으며, 예를 들어, 페니실린 내성 황색포도상구균, 반코마이신 내성 황색포도상구균, 메티실린 내성 황색포도상구균, 리팜피신 내성 황색포도상구균, 이소니아지드 내성 황색포도상구균, 가나마이신 내성 황색포도상구균일 수 있으며, 보다 바람직하게는 메티실린 내성 황색포도상구균 또는 반코마이신 내성 황색포도상구균일 수 있고, 가장 바람직하게는 메티실린 내성 황색포도상구균일 수 있으며, 본 발명의 범위가 이에 제한되지는 않는다.In the present invention, the Staphylococcus aureus may be an antibiotic resistant Staphylococcus aureus, for example, a Staphylococcus aureus resistant to penicillin, a Staphylococcus aureus resistant to vancomycin, a Staphylococcus aureus resistant to methicillin, a Staphylococcus aureus resistant to rifampicin, Staphylococcus aureus and kanamycin-resistant Staphylococcus aureus, more preferably methicillin-resistant Staphylococcus aureus or vancomycin-resistant Staphylococcus aureus, most preferably methicillin-resistant Staphylococcus aureus, Is not limited thereto.

본 발명에 있어서, 상기 포도상구균에 의한 감염성 질병은 유방염, 피부염, 패혈증, 화농성 질환, 식중독, 폐렴, 골수염, 농가진, 균혈증, 심내막염, 여드름, 수막염, 골관절염, 피부감염, 장염 및 요로감염으로 구성된 군으로부터 선택될 수 있지만, 이에 제한되는 것은 아니다.In the present invention, the infectious diseases caused by Staphylococcus aureus include mastitis, dermatitis, sepsis, pyogenic diseases, food poisoning, pneumonia, osteomyelitis, impetigo, bacteremia, endocarditis, acne, meningitis, osteoarthritis, skin infection, enteritis and urinary tract infection But is not limited thereto.

본 발명의 약학적 조성물은 1 × 103 내지 1 × 1010 PFU/mL의 박테리오파지를 포함하며, 바람직하게는 1 × 106 내지 1 × 109 PFU/mL의 박테리오파지를 포함한다. 본 발명에 사용된 용어, PFU (plaque forming unit)는 박테리오파지가 플라크를 형성하는 것을 수치화한 단위이다.The pharmaceutical composition of the present invention contains bacteriophage of 1 × 10 3 to 1 × 10 10 PFU / mL, preferably 1 × 10 6 to 1 × 10 9 PFU / mL of bacteriophage. The term " PFU (plaque forming unit) " used in the present invention is a unit in which bacteriophages form a plaque.

본 발명의 용어 예방이란 조성물의 투여로 질병을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.The term " prophylactic " of the present invention means all actions that inhibit disease or delay the onset of the disease by administration of the composition.

본 발명의 용어 치료란 조성물의 투여로 상기 질병의 증세가 호전되거나 상기 질병의 억제 또는 경감 및 이롭게 변경되는 모든 행위를 의미한다.The term " treatment " of the present invention refers to any action that improves or alleviates or alleviates the symptoms of the disease upon administration of the composition.

본 발명의 약학적 조성물은 약학적으로 허용 가능한 담체를 추가로 포함할 수 있다.The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier.

본 발명에서 용어, 약학적으로 허용 가능한 담체란 생물체를 자극하지 않고 투여 화합물의 생물학적 활성 및 특성을 저해하지 않는 담체 또는 희석제를 의미한다. 액상 용액으로 제제화되는 조성물에 있어서 허용되는 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로오스 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다.The term pharmaceutically acceptable carrier, as used herein, means a carrier or diluent that does not irritate the organism and does not interfere with the biological activity and properties of the administered compound. Examples of the pharmaceutical carrier which is acceptable for the composition to be formulated into a liquid solution include sterilized and sterile water, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, One or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, and a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.

본 발명의 약학적 조성물은 질환 부위에의 도포 또는 분무하는 방법으로 이용할 수 있으며, 그 밖에 비강 분무, 경구 투여 또는 비경구 투여를 통해 투여할 수도 있으며, 비경구 투여의 경우 정맥 내 투여, 복강 내 투여, 근육 내 투여, 피하 투여 또는 국부 투여를 이용하여 투여할 수도 있다.The pharmaceutical composition of the present invention can be used as a method of applying or spraying on a diseased site, or may be administered through nasal spray, oral administration or parenteral administration. In the case of parenteral administration, intravenous administration, intraperitoneal administration Administration, intramuscular, subcutaneous or local administration.

상기 비강 분무의 경우 일정량의 박테리오파지 SA7을 물에 희석하여 분무기나 분무 시스템을 통해 비강으로 흡수 되도록 할 수 있다. 상기 비강 분무를 위한 비강 분무제 또는 호흡기용 제형으로는 에어로졸제 등을 들 수 있다.In the case of the nasal spray, a certain amount of bacteriophage SA7 can be diluted in water and absorbed into the nasal cavity through a sprayer or spray system. Examples of the nasal spray agent for the nasal spray or the aerosol agent for the respiratory system are mentioned.

상기 비강 분무제 또는 호흡기용 제형은, 수분산된 농축물 또는 습윤 분말을 분산시키기 위한 추진제 및/또는 기타 첨가제를 추가로 포함할 수 있다.The nasal spray or respiratory formulation may further comprise a propellant and / or other additives for dispersing the water-dispersed concentrate or wet powder.

본 발명의 약학적 조성물의 적합한 도포, 분무 및 투여량은 제제화 방법, 투여 방식, 대상이 되는 동물 및 환자의 연령, 체중, 성, 질병 증상의 정도, 음식, 투여시간, 투여 경로, 배설 속도 및 반응 감음성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사나 수의사는 목적하는 치료에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다.The appropriate application, spray and dose of the pharmaceutical composition of the present invention may vary depending on factors such as formulation method, administration method, age, body weight, sex, disease symptom level, food, administration time, administration route, Response sensitivities and the like, and usually a skilled physician or veterinarian can easily determine and prescribe dosages effective for the desired treatment.

본 발명의 약학적 조성물을 유효성분으로 포함하는 경구 투여용 제형으로는, 예를 들어 정제, 트로키제, 로렌지, 수용성 또는 유성현탁액, 조제분말 또는 과립, 에멀젼, 하드 또는 소프트 캡슐, 시럽 또는 엘릭시르제로 제제화할 수 있다. 정제 및 캡슐 등의 제형으로 제제화하기 위해, 락토오스, 사카로오스, 솔비톨, 만니톨, 전분, 아밀로펙틴, 셀룰로오스 또는 젤라틴과 같은 결합제, 디칼슘 포스페이트와 같은 부형제, 옥수수 전분 또는 고구마 전분과 같은 붕괴제, 스테아르산 마그네슘, 스테아르산 칼슘, 스테아릴푸마르산 나트륨 또는 폴리에틸렌글리콜 왁스와 같은 윤활유를 포함할 수 있으며, 캡슐 제형의 경우 상기 언급한 물질 외에도 지방유와 같은 액체 담체를 더 함유할 수 있다.Examples of formulations for oral administration comprising the pharmaceutical composition of the present invention as an active ingredient include tablets, troches, lozenges, aqueous or oily suspensions, prepared powders or granules, emulsions, hard or soft capsules, syrups or elixirs It can be formulated into a zero. A binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin, an excipient such as dicalcium phosphate, a disintegrating agent such as corn starch or sweet potato starch, a disintegrant such as magnesium stearate , Calcium stearate, sodium stearyl fumarate or polyethylene glycol wax. In the case of a capsule formulation, in addition to the above-mentioned materials, a liquid carrier such as a fatty oil may be further contained.

본 발명의 약학적 조성물을 유효성분으로 포함하는 비경구 투여용 제형으로는, 피하주사, 정맥주사 또는 근육 내 주사 등의 주사용 형태, 좌제 주입방식 또는 호흡기를 통하여 흡입이 가능하도록 하는 에어로졸제 등 스프레이용으로 제제화할 수 있다. 주사용 제형으로 제제화하기 위해서는 본 발명의 조성물을 안정제 또는 완충제와 함께 물에서 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알의 단위 투여용으로 제제화할 수 있다. 에어로졸제 등의 스프레이용으로 제형화하는 경우, 수분산된 농축물 또는 습윤 분말이 분산되도록 추진제 등이 첨가제와 함께 배합될 수 있다.Examples of the formulations for parenteral administration containing the pharmaceutical composition of the present invention as an active ingredient include injection forms such as subcutaneous injection, intravenous injection or intramuscular injection, aerosol formulations such as a suppository injection method or a respiratory apparatus It can be formulated for spraying. For formulation into injectable formulations, the compositions of the present invention may be formulated as solutions or suspensions in water with stabilizers or buffers in water, and formulated for unitary administration of ampoules or vials. When formulated for spraying, such as an aerosol formulation, a propellant or the like may be formulated with the additive such that the water-dispersed concentrate or wet powder is dispersed.

또한, 본 발명은 상기 박테리오파지 SA7을 포함하는, 항생용 조성물을 제공한다. The present invention also provides an antibiotic composition comprising the bacteriophage SA7.

본 발명에서, 용어 항생용 조성물은 약제 형태로 동물에게 제공되어 균을 사멸시킬 수 있는 제제를 의미하며, 방부제, 살균제, 항생제 및 항균제를 총칭하는 것이다. In the present invention, the term antibiotic composition refers to a preparation which can be provided to an animal in the form of a drug to kill bacteria, and is collectively referred to as an antiseptic, a bactericide, an antibiotic and an antibacterial agent.

상기 동물은 인간을 포함한 포유동물 예를 들어, 돼지, 소 또는 가금류를 포함하는 개체를 의미하나, 이에 제한 되지는 않는다. 본 발명의 박테리오파지 SA7은 기존 항생제에 비하여 포도상구균에 대한 특이성이 매우 높으므로, 유익균은 죽이지 않고, 특정 병원균만 사멸시킬 수 있고, 약물 내성 내지 저항성을 유도하지 않아, 기존의 항생물질에 비하여 제품수명(life cycling)이 긴 신규 항생제로서 이용될 수 있다.The animal means an animal including, but not limited to, a mammal including a human, for example, a pig, a cattle or a poultry. The bacteriophage SA7 of the present invention has a higher specificity for Staphylococcus aureus than conventional antibiotics. Therefore, the bacteriophage SA7 of the present invention can kill only specific pathogens and does not induce drug resistance or resistance, (life cycling) can be used as a new antibiotic.

또한, 본 발명은 상기 박테리오파지 SA7을 포함하는, 사료 첨가용 조성물을 제공한다.In addition, the present invention provides a composition for feed addition comprising the bacteriophage SA7.

축산, 수산업에서 사용되는 사료 첨가용 항생제는 질병의 예방 목적으로 사용되고 있는데, 예방 목적의 항생제 투여는 내성균 발생 가능성을 높이고 가축에 잔류하는 항생제가 사람에게 전달될 수 있어서 문제이다. 항생제가 육류를 통해 인체에 흡수되면 항생제 내성을 유발해 질병의 확산을 부를 수도 있다. 또한, 사료에 섞여 먹이는 항생제의 종류가 많고 이는 다제 내성균 발생 확률이 높아지는 문제점이 있기 때문에 좀 더 자연 친화적이면서도 기존의 항생제의 사용에서 발생한 문제를 해결할 새로운 사료 첨가용 항생물질로서 본 발명의 상기 박테리오파지 SA7을 이용할 수 있다.Antibiotics for feed additive used in animal husbandry and fisheries are used for the prevention of diseases. The administration of antibiotics for prevention is problematic because it increases the possibility of producing resistant bacteria and antibiotics remaining in the livestock can be delivered to humans. If antibiotics are absorbed into the body through meat, they may cause antibiotic resistance and spread the disease. In addition, since there are many kinds of antibiotics mixed with feeds and there is a problem that the probability of occurrence of multidrug-resistant bacteria is high, antibiotics for new feed addition, which are more natural-friendly and solve problems caused by the use of existing antibiotics, Can be used.

또한, 본 발명은 상기 사료 첨가용 조성물을 포함하는 사료를 제공할 수 있으며, 본 발명의 사료는 박테리오파지를 사료 첨가제 형태로 따로 제조하여 사료에 혼합시키거나, 사료 제조 시 직접 첨가시켜 제조할 수 있다. 본 발명의 사료 내 박테리오파지는 액상 또는 건조상태일 수 있으며, 바람직하게는 건조된 분말형태이다. 건조방법은 통풍건조, 자연건조, 분무건조 및 동결건조가 가능하지만, 이에 제한되는 것은 아니다. 본 발명의 박테리오파지는 분말형태로 사료 중량의 0.05 내지 0.3 중량%, 바람직하게는 0.1 내지 0.3 중량%의 성분비로 혼합될 수 있다. 또한, 상기 사료는 본 발명의 박테리오파지 외에 사료의 보존성을 높일 수 있는 통상의 첨가제들을 추가로 포함할 수 있다.In addition, the present invention can provide a feed comprising the feed composition, and the feed of the present invention can be prepared by separately preparing bacteriophage as a feed additive and mixing the feed into the feed, . The bacteriophage in the feed of the present invention may be in a liquid or dry state, preferably in the form of a dried powder. Drying methods include, but are not limited to, air drying, natural drying, spray drying and freeze drying. The bacteriophage of the present invention may be mixed in powder form at a composition ratio of 0.05 to 0.3% by weight, preferably 0.1 to 0.3% by weight of the feed weight. In addition to the bacteriophages of the present invention, the feed may further include conventional additives that can enhance the preservability of the feed.

본 발명의 사료 첨가용 조성물에는 비병원성의 다른 미생물이 추가로 첨가될 수 있다. 첨가될 수 있는 미생물로는 단백질 분해 효소, 지질 분해효소 및 당 전환 효소를 생산할 수 있는 바실러스 서브틸리스(Bacillus subtilis)와 같은 고초균, 소의 위와 같은 혐기적 조건에서 생리적 활성 및 유기물 분해능이 있는 락토바실러스 균주(Lactobacillus sp.), 가축의 체중을 증가시키며 우유의 산유량을 늘리고 사료의 소화 흡수율을 높이는 효과를 보여주는 아스퍼질러스 오리자에(Aspergillus oryzae)와 같은 사상균 및 사카로미세스 세레비지에 (Saccharomyces cerevisiae)와 같은 효모로 구성된 군으로부터 선택될 수 있다.In the composition for feed addition of the present invention, microorganisms other than non-pathogenic microorganisms may be further added. Examples of microorganisms that can be added include lactobacilli such as Bacillus subtilis capable of producing proteolytic enzymes, lipolytic enzymes and glycosyltransferases, lactobacilli having physiological activity and organic resolution at anaerobic conditions such as bovine, ( Lactobacillus sp.), Filamentous fungi such as Aspergillus oryzae , which increase the body weight of livestock and increase the milk yield and increase digestion rate of feed, and Saccharomyces cerevisiae and yeast such as S. cerevisiae .

본 발명의 박테리오파지 SA7을 포함하는 사료에는 식물성으로는 곡물류, 근과류, 식품가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류, 곡물부산물류 등이 있으며, 동물성으로는 단백질류, 무기물류, 광물성류, 유지류, 단세포 단백질, 동물성 플랑크톤류, 남은 음식물 등이 있으며 이에 제한되는 것은 아니다.Examples of the feedstuffs containing bacteriophage SA7 of the present invention include cereals, muscle roots, food processing buses, algae, fibers, pharmaceutical buses, fats and oils, pastes, But are not limited to, proteins, inorganic materials, minerals, fats, single cell proteins, zooplankton, and remnants.

본 발명의 사료 첨가용 조성물에는 품질 저하를 방지하기 위하여 첨가하는 결착제, 유화제, 보존제 등이 포함될 수 있고, 효용 증대를 위하여 사료에 첨가하는 아미노산제, 비타민제, 효소제, 생균제, 향미제, 비단백태질소화합물, 규산염제, 완충제, 착색제, 추출제, 올리고당 등이 있으며, 그 외에도 사료 혼합제 등을 추가로 포함할 수 있다.The composition for feed addition of the present invention may contain a binder, an emulsifying agent, a preservative, etc. added to prevent deterioration of quality. An amino acid, a vitamin, an enzyme, a probiotic, a flavoring agent, A nitrogen compound, a silicate, a buffer, a coloring agent, an extracting agent, and an oligosaccharide. In addition, a feed mixture may be further included.

또한, 본 발명은 박테리오파지 SA7을 포함하는, 음용수 첨가제를 제공한다.The present invention also provides a drinking water additive comprising bacteriophage SA7.

본 발명의 음용수 첨가제는 상기 박테리오파지 SA7 또는 이를 포함하는 조성물을 음용수 첨가제 형태로 따로 제조하여 사료 또는 음용수에 혼합하는 방식으로 사용되거나, 음용수 제조 시 직접 첨가하는 방식으로 사용할 수 있다. 상기와 같이 음용수에 혼합하여 공급함으로써 지속적으로 포도상구균의 숫자를 감소시킬 수 있는 효과가 있다.The additive for drinking water of the present invention can be used either by preparing the bacteriophage SA7 or a composition containing the bacteriophage SA7 separately in the form of additive for drinking water, mixing it with feed or drinking water, or by directly adding it in the production of drinking water. As a result, the number of staphylococci can be continuously reduced by mixing them with drinking water.

본 발명에서 음용수는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 음용수를 사용할 수 있다.In the present invention, the drinking water is not particularly limited, and drinking water commonly used in the art can be used.

또한, 본 발명은 상기 박테리오파지 SA7을 포함하는, 소독제를 제공한다.The present invention also provides a disinfectant comprising the bacteriophage SA7.

포도상구균에 특이적 사멸능을 갖는 본 발명의 박테리오파지 SA7을 포함하는 소독제는 병원감염을 막기 위한 병원 및 보건용의 소독제로 유용하게 사용될 수 있고 일반 생활 소독제, 식품 및 조리 장소 및 설비의 소독제, 양계장, 축사 등의 건물, 축체, 음수, 깔짚, 난좌, 운반차량, 식기 등의 각종 생육 용품의 소독 등에 사용될 수 있다.The disinfectant containing the bacteriophage SA7 of the present invention having a specific killing effect on staphylococci can be effectively used as a disinfectant for hospital and public health to prevent hospital infection, and can be used as a general disinfectant, disinfectant for food and cooking places and facilities, , Disinfection of various kinds of growing equipments such as buildings such as houses, shaft bodies, negative water, litter, stairs, transportation vehicles, tableware, and the like.

또한, 본 발명은 상기 박테리오파지 SA7을 포함하는, 세척제를 제공한다.The present invention also provides a detergent comprising the bacteriophage SA7.

본 발명의 박테리오파지 SA7은 포도상구균에 특이적 사멸능을 가지므로, 포도상구균에 노출되었거나 노출될 가능성이 있는 인간, 돼지, 소 또는 가금류를 포함하는 개체의 피부 표면 또는 신체 각 부위 등을 세척하는 용도로도 사용될 수 있다.Since the bacteriophage SA7 of the present invention has a specific killing effect on Staphylococcus aureus, it can be used for washing skin surface or body parts of individuals including human, pig, cattle or poultry, Can also be used.

또한, 본 발명은 상기 박테리오파지 SA7을 개체에 투여하는 단계를 포함하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료 방법을 제공한다.The present invention also provides a method for preventing or treating an infectious disease caused by staphylococci, comprising the step of administering the bacteriophage SA7 to an individual.

본 발명에서, 용어 "개체"는 인간을 포함한 포유동물, 바람직하게는 가축류를 말하며, 가장 바람직하게는 소, 돼지 또는 가금류을 말하나, 이에 제한되는 것은 아니다.In the present invention, the term "individual " refers to a mammal including a human, preferably a livestock, most preferably a cow, a pig or a poultry.

상기 용어 "가축류"는 인간에 의하여 순화, 개량되어 사람과 함께 공동생활을 하는 유용한 동물을 지칭는 개념으로, 조류, 어류, 곤충류, 포유류를 모두 포함하는 개념으로, 상기 가축류는 돼지, 소, 닭, 말, 오리 및 개로 구성된 군에서 선택될 수 있으나, 이에 제한되는 것은 아니다.The term " livestock "refers to useful animals that are refined and improved by humans to live together with humans. The concept includes all birds, fishes, insects, and mammals. The livestock includes pigs, cows, Horse, duck, and dog, but is not limited thereto.

상기 용어 "가금류"는, 가축 중 조류에 속하는 동물을 총칭하여 이르는 개념이며, 상기 가금류는 닭, 오리, 꿩, 메추리, 타조, 거위 및 칠면조로 구성된 군에서 선택될 수 있으나, 이에 제한되는 것은 아니다.The term "poultry" is a concept that refers collectively to animals belonging to the domestic livestock, and the poultry may be selected from the group consisting of chicken, duck, pheasant, quail, ostrich, goose and turkey, but is not limited thereto .

본 발명의 방법은 포도상구균에 의한 유방염, 피부염, 패혈증, 화농성 질환, 식중독, 폐렴, 골수염, 농가진, 균혈증, 심내막염, 여드름, 수막염, 골관절염, 피부감염, 장염 및 요로감염이 발생했거나 발생 가능성이 있는 개체에 박테리오파지 SA7을 투여하는 단계를 포함한다. The method of the present invention can be used for the treatment or prevention of mastitis, dermatitis, sepsis, pyogenic diseases, food poisoning, pneumonia, osteomyelitis, impetigo, bacteremia, endocarditis, acne, meningitis, osteoarthritis, skin infection, enteritis and urinary tract infection And administering bacteriophage SA7 to the subject.

본 발명의 방법에서 상기 박테리오파지 SA7 또는 조성물은 약학적 제제의 형태로 동물에게 투여되거나, 가축의 사료 또는 음용수에 혼합하여 이를 섭식시키는 방법을 통해 투여될 수 있다.In the method of the present invention, the bacteriophage SA7 or composition may be administered to an animal in the form of a pharmaceutical preparation, or mixed with feed or drinking water of a livestock and fed to the animal.

본 발명의 방법에서 상기 박테리오파지 SA7 또는 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있으며, 구체적으로, 구강, 직장, 국소, 정맥 내, 복강 내, 근육 내, 동맥 내, 경피, 비측 내, 흡입 등을 통해 통상적인 방식으로 투여될 수 있다.In the method of the present invention, the administration route of the bacteriophage SA7 or composition can be administered through various routes of oral or parenteral administration as long as it can reach the target tissues. Specifically, the oral route, rectal, topical, intravenous, Intravenous, intramuscular, intraarterial, transdermal, intranasal, inhalation, and the like.

본 발명의 방법에 투여되는 상기 박테리오파지 SA7의 적합한 총 1일 사용량은 올바른 의학적 판단범위 내에서 처치의에 의해 결정될 수 있다는 것은 당업자에게 자명한 일이다. 특정 개체에 대한 구체적인 치료적 유효량은 달성하고자 하는 반응의 종류와 정도, 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여시간, 투여 경로 및 조성물의 분비율, 치료기간, 구체적 조성물과 함께 사용되거나 동시 사용되는 약물을 비롯한 다양한 인자와 의약 분야에 잘 알려진 유사 인자에 따라 다르게 적용하는 것이 바람직하다.It will be apparent to those skilled in the art that the appropriate total daily dose of the bacteriophage SA7 administered in the method of the present invention can be determined by treatment within the scope of sound medical judgment. The specific therapeutically effective amount for a particular individual will depend upon the type and extent of the response to be achieved, the age, weight, general health, sex and diet of the patient, the time of administration, the route of administration and the fraction of the route of administration, It is preferable to apply differently depending on various factors including drugs used or co-used and similar factors well known in the medical field.

본 명세서에서 달리 정의되지 않은 용어들은 본 발명이 속하는 기술분야에서 통상적으로 사용되는 의미를 갖는 것이다.Terms not otherwise defined herein have meanings as commonly used in the art to which the present invention belongs.

이하, 본 발명을 실시예, 제제예에 의해 상세히 설명한다. 단, 하기 실시예, 제제예는 본 발명을 예시하는 것일 뿐 본 발명의 내용이 하기 실시예, 제제예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples and Preparation Examples. However, the following examples and preparative examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following examples and preparative examples.

실시예Example 1:  One: 신규한New 박테리오파지의 분리 및 배양 Isolation and culture of bacteriophage

1.1 박테리오파지의 스크리닝 및 분리1.1 Screening and separation of bacteriophages

황색포도상구균(Staphylococcus aureus)에 특이적인 박테리오파지를 스크리닝 및 분리하기 위해서 용균반 분석을 수행하였다. 시료는 박테리오파지가 존재할 것으로 예상되는 도축장, 도계장 및 농장 부근의 하수로부터 채취하였으며, 박테리오파지 분리에 사용된 황색포도상구균은 (주)옵티팜에서 분리 동정된 것을 사용하였다.Sputum analysis was performed to screen and isolate bacteriophages specific for Staphylococcus aureus . Samples were collected from slaughterhouses, slaughterhouses and farms where bacteriophages were expected to be present. Staphylococcus aureus isolated from bacteriophage isolates was identified from Opti Pharm.

구체적으로, 채취한 시료를 황색포도상구균과 함께 35℃에서 하룻밤 동안 진탕배양 하였다. 상기 배양액을 4,000 rpm으로 20분간 원심분리한 후, 상등액을 공극(pore) 크기가 0.45 μm인 필터를 이용하여 여과하여 시료 여과액을 얻었다.Specifically, the collected sample was incubated with Staphylococcus aureus at 35 ° C overnight with shaking. The culture solution was centrifuged at 4,000 rpm for 20 minutes, and the supernatant was filtered using a filter having a pore size of 0.45 μm to obtain a sample filtrate.

전배양된 황색포도상구균 150 μL를 취해서 멸균된 튜브에 넣고 3-5 mL의 BHI 탑 아가(top agar)[뇌심장침출액(뇌 침출 솔리드(solids) 12.5 g, 소 심장 침출 솔리드 5.0 g, 프로테오스펩톤 10.0 g, 글루코스 2.0 g, NaCl 5 g, 인산나트륨 2.5 g/L)+ 0.6% 아가]를 첨가하여 잘 혼합한 후 미리 만들어 둔 2% BHI 아가 플레이트에 중층하였다. 실온에서 30분간 방치한 후 상기 시료 여과액을 각각 10 μL씩 점적하고, 다시 실온에서 30분간 방치한 후 35℃에서 24시간 동안 배양하여 박테리오파지의 유무를 확인하였다.150 μL of pre-cultured Staphylococcus aureus was placed in a sterile tube and placed in a sterile tube and incubated with 3-5 mL of BHI top agar [brain heart leachate (brain leaching solids 12.5 g, bovine heart leaching solids 5.0 g, 10.0 g of streptone, 2.0 g of glucose, 5 g of NaCl and 2.5 g / L of sodium phosphate) + 0.6% of agar], and the mixture was layered on 2% BHI agar plates previously prepared. After allowing to stand at room temperature for 30 minutes, the sample filtrate was dropped by 10 μL each. Each sample was left at room temperature for 30 minutes and then cultured at 35 ° C. for 24 hours to confirm presence or absence of bacteriophages.

박테리오파지의 존재를 확인한 시료로부터 박테리오파지를 순수 분리하기 위해서 소프트 아가 오버레이(soft agar overlay)법을 이용하였다. 박테리오파지가 존재하는 것으로 확인된 시료를 식염수로 적절히 희석하여 각 희석단의 시료 희석액 100 μL를 취하고, 대상 세균(황색포도상구균) 배양액 150 μL에 혼합한 후 0.6% BHI 탑 아가 3 mL을 첨가하여 잘 혼합한 뒤, 미리 만들어 둔 2% BHI 아가 플레이트에 중층하여 방치한 후 35℃에서 24시간 배양하였다. 배양한 각 플레이트에서 형성된 용균반을 확인한 후, 이를 선택하여 400 μL의 SM 완충액 (NaCl 5.8 g/L; MgSO47H2O 2 g/L; 1M Tris-HCl (pH 7.5) 50 mL)에 현탁하고, 실온에서 4시간동안 방치하였다. 상기 박테리오파지액 100 μL를 0.6% BHI 탑 아가와 세균 배양액 500 μL와 혼합한 뒤 150 mm 지름의 BHI 플레이트에 분주하여 중층한 후 완전히 용균이 일어날 때까지 35℃에서 배양하였다. 배양이 종료된 후, BHI 플레이트에 15 mL의 SM 완충액을 가하고 실온에서 4시간 동안 천천히 교반하면서 박테리오파지 용액을 회수한 후 4,000 rpm으로 20분간 원심분리하여 상등액만 취하고 이를 0.45 μm 필터로 여과하여 최종 박테리오파지 용액을 회수하였다. 이렇게 얻어진 최종 박테리오파지의 용균반을 확인한 결과를 도 1에 나타내었다.A soft agar overlay method was used to isolate the bacteriophage from the sample which confirmed the existence of the bacteriophage. A sample of which the bacteriophage was confirmed to be present was diluted appropriately with saline, 100 μL of sample dilution of each dilution stage was taken, mixed with 150 μL of the bacterial (Staphylococcus aureus) culture, and 3 mL of 0.6% BHI topa After mixing, the mixture was allowed to stand in a 2% BHI agar plate that had been previously prepared, followed by incubation at 35 ° C for 24 hours. After incubation, the supernatant was added to 400 μL of SM buffer (NaCl 5.8 g / L; MgSO 4 7H 2 O 2 g / L; 1M Tris-HCl (pH 7.5) And allowed to stand at room temperature for 4 hours. 100 .mu.l of the bacteriophage solution was mixed with 500 .mu.l of 0.6% BHI top agar and bacterial culture, and the mixture was divided into 150-mm-diameter BHI plates and incubated at 35.degree. C. until lysis occurred. After incubation, 15 mL of SM buffer was added to the BHI plate, and the bacteriophage solution was recovered while slowly stirring at room temperature for 4 hours. The supernatant was centrifuged at 4,000 rpm for 20 minutes. The supernatant was collected by filtration through a 0.45 μm filter, The solution was recovered. FIG. 1 shows the result of checking the thus obtained final bacteria bacterium.

1.2 박테리오파지의 대량 배양 및 정제1.2 Bulk culture and purification of bacteriophages

상기 실시예　1.1에서 확인한 황색포도상구균 특이적인 박테리오파지를 대량 배양하기 위하여, 1.1에서 회수한 최종 박테리오파지 배양액을 1.0x107 PFU/mL로 희석한 후 전배양된 황색포도상구균 1.0x109 CFU/mL과 혼합하여 MOI (Multiplicity of infection)가 0.01이 되도록 하여 35℃에서 120 rpm으로 9시간 배양하였다. 배양이 종료된 후 배양액 전량을 6,000 rpm으로 30분간 원심분리하여 상등액을 수득하였고, 이를 0.2 μm 필터로 여과하여 최종 박테리오파지 배양액을 회수하였다. 분리된 박테리오파지를 박테리오파지 SA7(Bacteriophage SA7)으로 명명하고, 2016년 7월 22일 한국미생물보존센터(Korean Culture Center of Microorganisms, 서울, 한국)에 기탁하고 수탁번호 KFCC11673P를 부여받았다.In order to mass-culture the S. aureus-specific bacteriophage identified in Example 1.1 above, the final bacteriophage culture recovered at 1.1 was diluted to 1.0 x 10 < 7 > After dilution with PFU / mL, the cells were mixed with 1.0 × 10 9 CFU / mL of pre-cultured Staphylococcus aureus and cultured at 35 ° C. and 120 rpm for 9 hours to obtain MOI (multiplicity of infection) of 0.01. After the culture was completed, the whole culture was centrifuged at 6,000 rpm for 30 minutes to obtain a supernatant, which was then filtered with a 0.2 μm filter to recover the final bacteriophage culture. The isolated bacteriophage was named bacteriophage SA7 (Bacteriophage SA7) and deposited on July 22, 2016 at the Korean Culture Center of Microorganisms (Seoul, Korea) and received the accession number KFCC11673P.

실시예Example 2: 박테리오파지 SA7의 전체 유전자 분석 2: Whole gene analysis of bacteriophage SA7

박테리오파지 SA7의 전체 유전자를 분석하기 위해, 박테리오파지 SA7 배양액에 20 mM EDTA, 50 μg/mL의 프로테나아제 K, 0.5% (w/v) SDS를 가한 후, 50℃에서 1시간 동안 정치하였다. 동량의 페놀-클로로포름-이소프로필 알코올 (25:24:1)과 혼합한 후 실온에서 12,000 rpm으로 10분간 원심분리하여 상등액을 회수하고, 상기 상등액에 3M 소듐 아세테이트를 전체 부피의 10%(v/v)가 되도록 가한 후 혼합하였다. 여기에 2배 부피의 차가운 95% 에탄올을 가하여 혼합한 뒤 -20℃에서 1시간 동안 정치하였다. 반응이 끝난 후 0℃에서 10분간 12,000 rpm으로 원심분리하여 침전물을 획득하였고, 차가운 70% 에탄올로 2회 세척한 뒤 에탄올을 완전히 제거하여 DNA 펠렛을 회수하였다. 회수한 펠렛을 최종 부피가 50 μL가 되도록 TE 완충액 (Tris-EDTA, pH 8.0)에 용해시킨 후 DNA 농도를 측정하였다. 전체 유전자 분석을 위해 PacBioRSII 를 이용하여 유전자 시퀀싱을 시행하였다 (마크로젠, 한국).To analyze the entire gene of bacteriophage SA7, 20 mM EDTA, 50 μg / mL proteinase K and 0.5% (w / v) SDS were added to the bacteriophage SA7 culture medium, and the mixture was allowed to stand at 50 ° C. for 1 hour. After mixing with an equal amount of phenol-chloroform-isopropyl alcohol (25: 24: 1), the supernatant was recovered by centrifugation at 12,000 rpm for 10 minutes at room temperature, and 3M sodium acetate was added to the supernatant in a total volume of 10% v) and then mixed. The mixture was mixed with 2 volumes of cold 95% ethanol, and the mixture was allowed to stand at -20 DEG C for 1 hour. After the reaction was completed, the precipitate was collected by centrifugation at 12,000 rpm for 10 minutes at 0 ° C., washed twice with cold 70% ethanol, and then the ethanol was completely removed to recover the DNA pellet. The recovered pellet was dissolved in TE buffer (Tris-EDTA, pH 8.0) to a final volume of 50 μL, and the DNA concentration was measured. Gene sequencing was performed using PacBioRSII for whole gene analysis (Macrogen, Korea).

시퀀싱 결과, 박테리오파지 SA7의 전체 유전자의 크기는 34,730 bp 이며, GC함량이 34%, 전체 ORFs의 수는 52개임을 확인하였다. 분석한 박테리오파지 SA7의 전체 유전자 서열을 서열번호 1로 나타내었다.As a result of sequencing, it was confirmed that the total gene of bacteriophage SA7 was 34,730 bp, the GC content was 34%, and the total ORFs were 52. The entire gene sequence of the bacteriophage SA7 analyzed is shown in SEQ ID NO: 1.

실시예Example 3: 박테리오파지 SA7의 형태학적 특성 3: Morphological characteristics of bacteriophage SA7

박테리오파지 SA7의 형태학적 특성을 알아보기 위해, 그리드를 고정한 뒤 0.01%의 BSA 용액 (Bovine serum albumin) 10 μL를 처리하고 10 초 후 필터 페이퍼로 제거하였다. 준비된 박테리오파지 SA7을 10 μL 취하여 그리드 위에 분주하고 1~2분간 방치 후 필터 페이퍼로 제거하는 과정을 2회 반복한 뒤, 포스포텅스텐산(phosphotungstic acid) 용액 10μL를 시료를 처리한 그리드 위에 처리하고 5분간 방치 한 후 필터 페이퍼로 제거하는 과정을 2회 반복하여 염색한 다음 투과전자현미경 (Carl Zeiss transmission electron microscope, 80 kV, 120,000~200,000)으로 검경하였으며 그 결과를 도 2에 나타내었다.To determine the morphological characteristics of bacteriophage SA7, 10 μL of 0.01% BSA solution (Bovine serum albumin) was applied and fixed with filter paper after 10 seconds. 10 μL of the prepared bacteriophage SA7 was dispensed onto the grid and allowed to stand for 1 to 2 minutes and then removed with a filter paper. This procedure was repeated twice. Then, 10 μL of phosphotungstic acid solution was treated on the sample-treated grid, The filter paper was dyed repeatedly twice. The result was observed with a Carl Zeiss transmission electron microscope (80 kV, 120,000 ~ 200,000). The results are shown in FIG.

도 2에 나타낸 바와 같이, 박테리오파지 SA7은 은 100-150 nm의 크기로, 정이십면체의 머리를 가지며 수축성 꼬리가 있는 형태인 마이오비리데(Myoviridae)형태에 속함을 확인하였다.As shown in Fig. 2, bacteriophage SA7 was found to belong to the form of Myoviridae having a size of 100-150 nm of silver and having a truncated dichroic head and a contractile tail.

실시예Example 4: 박테리오파지 SA7의 단백질 패턴 분석 4: Protein pattern analysis of bacteriophage SA7

박테리오파지 SA7의 단백질 패턴을 분석하기 위해, 1.0x1010 PFU/mL로 준비된 박테리오파지 SA7 40 μL를 10 μL의 5X 로딩 완충액과 혼합하고, 10분간 끓인 다음 12.5% SDS-PAGE를 수행하였다. SDS-PAGE 수행 후 단백질 전기영동 결과를 도 3에 나타내었다.To analyze the protein pattern of bacteriophage SA7, 40 μL of bacteriophage SA7 prepared with 1.0 × 10 10 PFU / mL was mixed with 10 μL of 5X loading buffer, boiled for 10 minutes, and then subjected to 12.5% SDS-PAGE. The results of SDS-PAGE and protein electrophoresis are shown in FIG.

도 3에 나타낸 바와 같이, 박테리오파지 SA7은 110 kDa, 50 kDa, 40 kDa, 32 kDa 그리고 30 kDa 크기의 주요 단백질을 가지는 것을 확인하였다.As shown in Fig. 3, bacteriophage SA7 has major proteins of 110 kDa, 50 kDa, 40 kDa, 32 kDa and 30 kDa in size.

실시예Example 5: 박테리오파지 SA7의 감염성 조사 5: Investigation of infectivity of bacteriophage SA7

5.1 박테리오파지 SA7의 황색포도상구균에 대한 감염성 조사5.1 Infection of Staphylococcus aureus with Bacteriophage SA7

박테리오파지 SA7의 황색포도상구균(Staphylococcus aureus)에 대한 감염성을 소프트 아가 오버레이법을 통해 확인하였고, 그 결과를 표 1에 나타내었다.The infectivity of bacteriophage SA7 against Staphylococcus aureus was confirmed by soft agar overlay method, and the results are shown in Table 1.

Figure pat00001
Figure pat00001

상기 표 1에 나타낸 바와 같이, 박테리오파지 SA7은 황색포도상구균에 대해 탁월한 용균활성을 나타냄을 확인하였다.As shown in Table 1, it was confirmed that bacteriophage SA7 exhibits excellent lytic activity against Staphylococcus aureus.

5.2 박테리오파지 SA7의 다양한 세균에 대한 감염성 조사5.2 Investigation of infectivity of bacteriophage SA7 on various bacteria

박테리오파지 SA7의 메티실린(methicillin) 내성 황색포도상구균에 대해서 용균활성을 나타내는지 확인하기 위하여, 아시아태평양 감염연구소로부터 분양받은 인체 유래 메티실린 내성 황색포도상구균를 대상으로 혈액 아가 평판배지(blood agar plate)를 이용하여 소프트 아가 오버레이법을 통해서 감염성을 확인하였다. 그 결과는 표 2에 나타내었다.In order to confirm that the bacteriophage SA7 exhibited lytic activity against methicillin-resistant Staphylococcus aureus, a blood agar plate was prepared from human-derived methicillin-resistant Staphylococcus aureus from the Asia Pacific Institute for Infectious Diseases And infectivity was confirmed by soft agar overlay method. The results are shown in Table 2.

Figure pat00002
Figure pat00002

표 2에 나타낸 바와 같이, 박테리오파지 SA7은 메티실린 내성 황색포도상구균에 대해서도 탁월한 용균활성을 나타냄을 확인하였다.As shown in Table 2, it was confirmed that bacteriophage SA7 exhibits excellent lytic activity against methicillin-resistant Staphylococcus aureus.

또한, 다양한 세균에 대해서 용균활성을 나타내는지 확인하기 위하여 ㈜옵티팜에서 분리하여 보유하고 있는 균주와 미생물 자원센터 등에서 분양받은 균주를 대상으로 소프트 아가 오버레이법을 통해서 감염성을 확인하였다. 그 결과를 표 3에 나타내었다.In order to confirm that the bacteria exhibit lytic activity against various bacteria, the strains isolated from OptiParm Co., Ltd. and the strains distributed in the microbiological resource center were infected through the soft agar overlay method. The results are shown in Table 3.

Figure pat00003
Figure pat00003

표 3에 나타낸 바와 같이, 황색포도상구균 외에도 다른 미생물을 대상으로 감수성 검사를 진행한 결과, 박테리오파지 SA7은 Salmonella Typhimurium, Escherichia coli , Bacillus cereus 또는 Lactobacillus plantarum 등 다른 속의 세균에 대해서는 용균활성이 없는 것을 확인하였다.As shown in Table 3, the susceptibility test was performed on other microorganisms other than Staphylococcus aureus. As a result, bacteriophage SA7 was found to be Salmonella Typhimurium , Escherichia It was confirmed that there was no lytic activity for bacteria of other genus such as E. coli , Bacillus cereus or Lactobacillus plantarum .

따라서, 본 발명의 박테리오파지 SA7은 포도상구균속에 특이적으로 용균활성을 나타내는 박테리오파지임을 확인하였다.Therefore, it was confirmed that the bacteriophage SA7 of the present invention is a bacteriophage exhibiting a lytic activity specifically in Staphylococcus aureus.

실시예Example 6: 박테리오파지 SA7의 pH 안정성 조사 6: Investigation of pH stability of bacteriophage SA7

박테리오파지 SA7의 pH 안정성을 확인하기 위하여, 다양한 pH 범위(pH 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)에서 박테리오파지의 수를 측정하였다. 소듐 아세테이트 완충액, 소듐 포스페이트 완충액, Tris-HCl을 이용하여 각각의 pH에 맞게 조제한 후 1 mL로 분주하여 준비하였다. 5.5x108 PFU/mL로 준비한 박테리오파지 SA7 배양액 10 μL을 상기 용액에 첨가하여 2시간 동안 상온에서 방치하였다. 방치 후 각 반응액을 단계희석하여 소프트 아가 오버레이법에 의한 타이터(titer) 측정을 수행한 결과를 도 4에 나타내었다.In order to confirm the pH stability of bacteriophage SA7, the number of bacteriophages was measured in various pH ranges (pH 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). Sodium acetate buffer, sodium phosphate buffer, and Tris-HCl were added to each pH-adjusted solution, and the mixture was divided into 1 mL. 10 μL of the bacteriophage SA7 culture prepared to 5.5 × 10 8 PFU / mL was added to the above solution and left at room temperature for 2 hours. After leaving the solution, each reaction solution was diluted stepwise and a titer measurement was performed by soft agar overlay method. The result is shown in FIG.

도 4에 나타낸 바와 같이, pH 4-11의 범위에서는 박테리오파지 SA7이 2시간 동안 안정한 것으로 확인되었으며, pH 2에서는 박테리오파지의 수가 2.5 log, pH 3에서는 1 log가 감소됨을 확인하였다. As shown in FIG. 4, it was confirmed that bacteriophage SA7 was stable for 2 hours in the range of pH 4-11, and it was confirmed that at pH 2, the number of bacteriophages was 2.5 log, and at pH 3, 1 log was decreased.

따라서, 본 발명의 박테리오파지 SA7은 pH 4-11의 범위에서 안정함을 확인하였으므로, 박테리오파지 SA7은 pH 안정성이 우수한 박테리오파지임을 알 수 있다.Therefore, it was confirmed that the bacteriophage SA7 of the present invention is stable in the pH range of 4-11, so that bacteriophage SA7 is a bacteriophage having excellent pH stability.

실시예Example 7: 박테리오파지 SA7의 열 안정성 조사 7: Investigation of thermal stability of bacteriophage SA7

박테리오파지 SA7의 열 안정성을 확인하기 위하여, 다양한 온도 범위(40℃, 50℃, 60℃, 그리고 70℃)에서 박테리오파지의 수를 측정하였다. 박테리오파지 SA7 배양액(1.5x107 PFU/mL) 5mL을 멸균된 튜브에 분주한 후 박테리오파지를 첨가하여 2시간 동안 각 온도에서 방치하였다. 방치 후 각 반응액을 단계희석하여 소프트 아가 오버레이법에 의한 타이터 측정을 수행한 결과를 도 5에 나타내었다.In order to confirm the thermal stability of bacteriophage SA7, the number of bacteriophages was measured in various temperature ranges (40 ° C, 50 ° C, 60 ° C and 70 ° C). 5 mL of bacteriophage SA7 culture (1.5 x 10 7 PFU / mL) was dispensed into sterile tubes and bacteriophage was added and left at each temperature for 2 hours. After leaving the solution, each reaction solution was diluted stepwise and the titer was measured by soft agar overlay method. The result is shown in Fig.

도 5에 나타낸 바와 같이, 40-70℃의 범위에서는 30분까지는 안정한 것을 확인하였다. 따라서, 본 발명의 박테리오파지 SA7은 내열성이 우수한 박테리오파지임을 알 수 있다.As shown in Fig. 5, it was confirmed that it was stable up to 30 minutes in the range of 40-70 占 폚. Therefore, it can be seen that the bacteriophage SA7 of the present invention is a bacteriophage having excellent heat resistance.

상기 실험으로부터 박테리오파지 SA7은 포도상구균에 대한 특이성이 매우 높고, 포도상구균에 감염하여 포도상구균 내에서 증식함으로써 용균 활성이 우수하고 물리화학적 자극에 강하다는 장점을 가지고 있음을 확인하였다. 또한 본 발명의 박테리오파지 SA7은 사람, 동물, 식물 등 세균 외의 다른 숙주에는 감염되지 않으므로, 항생제의 오남용으로 인한 항생제 내성균의 문제점, 식품 내의 항생제의 잔류 문제, 광범위한 숙주범위의 문제점을 해결할 수 있는 장점이 있다. 따라서, 본 발명의 박테리오파지 SA7은 포도상구균에 의한 감염성 질병의 예방 또는 치료, 항생용 조성물, 사료 첨가용 조성물, 사료, 소독제, 또는 세척제 분야에서 다양하게 사용될 수 있다.From the above experiments, it was confirmed that bacteriophage SA7 has a high specificity for Staphylococcus aureus, has an advantage of being excellent in lytic activity and strong against physicochemical stimulation by proliferation in Staphylococcus aureus by infecting Staphylococcus aureus. In addition, the bacteriophage SA7 of the present invention is not infected by any host other than bacteria such as humans, animals and plants, and thus has an advantage of being able to solve problems of antibiotic resistant bacteria caused by misuse of antibiotics, residual antibiotics in food, have. Therefore, the bacteriophage SA7 of the present invention can be used variously in the field of prevention or treatment of infectious diseases caused by staphylococci, compositions for antibiosis, composition for feed addition, feed, disinfectant, or detergent.

비록 본 발명이 상기에 언급된 바람직한 실시예로서 설명되었으나, 발명의 요지와 범위로부터 벗어남이 없이 다양한 수정이나 변형을 하는 것이 가능하다. 또한 첨부된 청구 범위는 본 발명의 요지에 속하는 이러한 수정이나 변형을 포함한다.Although the present invention has been described in terms of the preferred embodiments mentioned above, it is possible to make various modifications and variations without departing from the spirit and scope of the invention. It is also to be understood that the appended claims are intended to cover such modifications and changes as fall within the scope of the invention.

이하 본 발명의 박테리오파지 SA7을 포함하는 약학적 조성물의 제제예를 설명하나, 본 발명을 한정하고자 함이 아니고 단지 이를 구체적으로 설명하고자 함이다.Hereinafter, formulation examples of the pharmaceutical composition including the bacteriophage SA7 of the present invention will be described, but the present invention is not intended to be limited thereto, but will be described specifically.

제제예Formulation example 1: 의약품의 제조 1: Manufacture of medicines

1.1 주사제의 제조1.1 Manufacture of Injection

박테리오파지 SA7 1 × 106 PFU/mLBacteriophage SA7 1 x 10 6 PFU / mL

주사용 멸균 증류수 적량Sterile sterilized water for injection

pH 조절제 적량pH adjuster

통상의 주사제의 제조방법에 따라 1 앰플당(2 mL) 상기의 성분 함량으 로 제조한다.(2 mL) per 1 ampoule according to the usual injection preparation method. .

1.2 1.2 액제의Liquid 제조 Produce

박테리오파지 SA7 1 × 106 PFU/mLBacteriophage SA7 1 x 10 6 PFU / mL

설탕 20gSugar 20g

이성화당 20g20g per isomer

레몬향 적량Lemon incense quantity

정제수를 가하여 전체 1,000 mL로 맞추었다. 통상의 액제의 제조방법에 따라 상기의 성분을 혼합한 다음, 갈색병에 충전하고 멸균시켜 액제를 제조한다.Purified water was added and the total volume was adjusted to 1,000 mL. The above components are mixed according to a usual method for producing a liquid agent, and then filled in a brown bottle and sterilized to prepare a liquid agent.

1.3 정제의 제조1.3 Manufacture of tablets

박테리오파지 SA7 1 × 106 PFU/mLBacteriophage SA7 1 x 10 6 PFU / mL

옥수수전분 100mgCorn starch 100 mg

유당 100mgLactose 100mg

스테아린산 마그네슘 2mgMagnesium stearate 2 mg

상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.

한국미생물보존센터(국내)Korea Microorganism Conservation Center (Domestic) KFCC11673PKFCC11673P 2016072220160722

<110> Optipharm.CO.,LTD <120> Novel Staphylococcus specific bacteriophage SA7 and antibacterial composition comprising the same <130> 1-20P <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 34730 <212> DNA <213> Unknown <220> <223> Bacteriophage SA7 <400> 1 atgcaagcat tacaaacatt taattttaaa gagctaccag taagaacagt agaaattgaa 60 aacgaacctt attttgtagg aaaagatatt gctgagattt taggatatgc aagagcagac 120 aatgccatta gaaatcatgt tgatagcgag gacaagctga cgcaccaatt tagtgcatca 180 ggtcaaaaca gaaatatgat cattatcaac gaatcaggat tatacagtct aatcttcgat 240 gcttctaaac aaagcaaaaa cgaaaaaatt agagaaaccg ctagaaaatt caaacgctgg 300 gtaacatcag atgtcctacc agctattcgc aaacacggta tctacgcaac agacaatgta 360 attgaacaaa cattaaaaga tccagactac atcattacag tgttgactga gtataagaaa 420 gaaaaagagc aaaacttact tttacaacaa gaaatcggag agctaaaacc caaagcagat 480 tatgttgatg aaatcttaaa atcaactggc acattagcta caactcaaat cgcggcagac 540 tacggtatat cagcacaaaa gttaaacaaa ctactacacg aagctagatt acaacgaaaa 600 gtaaataaac agtgggtgct ttactcagaa cacatgggca agagttacac agaatcagac 660 actatagcaa ttgtacgctc tgacggtaga gaagacacag ttttacaaac tagatggaca 720 caaaaaggca gattgaaaat acatgaaatc atgactgaat tcggttatga agctaacgta 780 actgcttaac aggaggaacg aacaatgcaa gctcaaaaca aaaaagtcat ctattactac 840 tatgacgaag aaggtaatag acgactatta tcaattggga atttggaaca ttatttatta 900 gcagatatca aatcaaggtt tgatttatat aaaaagaaaa tacctgactt agataatctg 960 ttcgttcaaa tagacggtgt tgaatttaaa ttactatagc ccgagcatct tgttaacgac 1020 tgacgatgcg atttgttgaa ttatagggat tgaaaccgaa gaaacttttg acgctttagc 1080 tttagtttct ctccaaactt cgacatctct aacatcatcc aaaaggttgt gacctgaaaa 1140 attcatatgt ttaacaaaat aaccttccat atagaattca gcgtctatat aacctgcacc 1200 ggtcaattgt ttaacagtgt attcgatgtc ttcacgtgag aaatttttaa ttgtattttc 1260 taggtcttca ttatctagaa cattatttaa ttttaaatca ctctctataa ctaaaagaac 1320 ttcacgtatg caatcgtgtt ttaacttcat acgaattcac ctccttaata ggagtatagc 1380 agaaaggagc ataaacaata tggaagatat gaaagaactt tattctttaa aaatccaaaa 1440 gaagaattta aataataaac aaaagaattt aatgtctgta attaatcaat gtattgaact 1500 agaaaaattt tcttacactg aaattaaaaa agttctctac ctaattgata gagaacaaaa 1560 gtatttagct aataaccgca gaaaaacata agttaaaaat aatctaactc ggactgctgg 1620 caatcttcta aatatttttc atactgattt ttagttccgc ccagaacgta ttcagtattg 1680 tagtacgctt gtccattatc caaaatttta actaattttg taccaacatg aacgatatcc 1740 caaccttctt ttaacagatc gttggctgca tcattagcta aatcgtcatc gaaagacaaa 1800 aggtgatagt agtttttcat aatattcacc tcctctctgt aggagataac aacattatac 1860 acgaaaggaa tgatagaaat gccacatgta ttaaacgtaa ccgttccaat acctgaaaca 1920 catgtactta tcacaaaaga tgaatatgat gagctaattg gttatacatt agaccctgta 1980 tggaacatga gtgacttaaa gaagaaatta aaaattgcat ctgatgagac tatcaaggac 2040 agattactat ttcatcctag atttgaaaaa gaactaagag cgcaaggaat tgtgcattac 2100 ccagatgaga attttaatcg ctggagattt aacgcaagaa agatgaataa attcgtcgat 2160 gagcatttca atgaaatata taaggagaga ataaaatgag caacatttat aaaagctacc 2220 tagtagcagt actgtgcttt acagtcttag caattgtact tatgccgttt ctatacttca 2280 ctactgcatg gtcgattgcg ggattcgcaa gtatcgcaac attcatattt tataaggaat 2340 acttttatga agaataaaaa aactgttact cacggcaatg agtaacagtc taaacaatta 2400 gaaaattaat gcatattcaa tataaaacga aataaaggaa gtgtcaacaa tgtactacaa 2460 aattggcgat gtatgtcaaa aagtaattaa tgtagacgga ttcgatttta aattagcagt 2520 taagaaacaa gattacagca ttctagtgaa tgtcttagat ttagaagata gatttatcga 2580 cggtataaat ataacagatg agaatgatct atacacagca ttagacatat taaatcaatc 2640 tatttatgaa tggattgaag agaacacaga cgaaagagac aggctaatta acttagtcat 2700 gagatggtag gtataagcat gagagataca gaaagaaata tattgaatat ttttaagacg 2760 ttattcgacg aatatacttt gtcaaaccaa cgagcattat tggaaattga acgtaatcat 2820 cacggatact tatcgattaa tttcttgcac tatcacgaca gttacaaaac gaacaataag 2880 cttgtacaga tacatgaaat caatccggac agccacgaac gaataaaaaa tttaattatc 2940 gaggtgttaa gaggtcaccg aaagattaaa aaaggagcat gatgatggat ataaaaataa 3000 ataagctaac aatatcaaac tttgctggaa tcaaagaaga aagctttaac tttgacggta 3060 aagacacaaa aatatacggc aataatgcga ctggtaagac tacgactgca accgcattac 3120 aatggctgct tttcgataaa ggtttggacg gatcaaccaa atcatttaac cctgtacctt 3180 taaacgaaaa aaacgaagaa aattatgagt taattccgac tgttttcgca gaatttgaaa 3240 tcgacggaaa aataacgact ttcaaaaaag agtcacatcc taaatacaca ataaatcaaa 3300 agacgaatcg caaggaatac tcacgaagta gaacaaagaa acaatatatc aatgatgaat 3360 caataaaagt aaaggattat aaagctcgta ttgatgaact aattgatgaa gatgtattca 3420 agttgattac aaatccccaa gcatttaatt tactcgattg gaagaaacga agaagtttgt 3480 tatttgaaat tgcaaaacca attaatgatg aggatgtcat taaaacaaat aacgacttta 3540 aaaaattaaa taatattctt ggtgatcatg aaattgaaac aaagaaaaag attcttactg 3600 acaagataaa gcagattaac aaagacatca aagatattcc gatacgtatt aatcaaacac 3660 aacaaaataa gcaggatgta ccagaattcg ataacgatag atacgcaatt atcaaacaag 3720 aaattgagca acttgaaaat gagcgtatag atattcaaaa cggtaaggaa gaaattaatt 3780 tgcgtaatca attagctgat aaacaatcag aattgaaacg catagaagac aataacagcg 3840 caagtaatga gaacaaaatt tatgctttaa caaatgagtt acacgttgaa aatggaacgg 3900 ttgcgaacct taaaacgaga ttaaagcaaa acaaacaaca aattacgcat gaagaaaata 3960 gacgtaatca attattggaa aatcacaaag gactaaaaag tgatttagaa aaatctaaaa 4020 atcaaaaatt tgaacatctt gatgacaatg tatgtagctg ttgcggtcaa cagttaccaa 4080 ctgaacaagt gaatgaggca agagaaaaag ctttacagaa attcaatgta aaaaaatcga 4140 aagaattaga aacaatacaa acatctatca atcacattat ttcagaagga aagaaaataa 4200 agccaatcat cgagaagtta gaggatgaca acaataatct acaaattaaa atcaacgaag 4260 cagaagagcg ttcagcaaga atacaaaaca aaattaataa gttgaaaacg actcatgttg 4320 acgttacaca aactgacgaa tacaaagcag taatgttaga gataaacgag attaatcaaa 4380 aacgctcgaa cattaggaaa actattcaag ataacgtttc aggaatagat gacaaaataa 4440 gcgaacttac tcaagaaaaa tcagaaattg aagtgtcaag atcaatcgaa aaatcaaata 4500 aacatctaga tgatgttatt tctgaattaa gaaatgaaga agatagatta ttggatgaaa 4560 aagaaaagta ttcacatgac ctttatatct taaaagaatt tacaacaaca aaagtcaaaa 4620 tgcttactga aaatatcaat aatgaatttg agattgctga atttaagtta ttcaatacct 4680 tagttaacgg cgaattagaa gaaacatgtt ccacaacggt taacggcgtc gaatacgaca 4740 gcggtttaaa taacgcctca agaattaatg ttggcttaga tatcatcaat acactgtcaa 4800 aacattttaa agttacagcg ccaatattta ttgataatgc tgaatcagta acagagctta 4860 tcaaaacaga atcacaacaa attcaattga tagtaaatga acaagataaa aaaataagaa 4920 tggagactat ataaaatgac tgaaaataat aaattacaaa ctattgaaca acaattagta 4980 caagaaaaga acgtatctga caacgtatta aacaaagtga gagttttaga gtcacaaggc 5040 aatttggaat tgccaaatga ttattcacca agtaatgcca tgaaacaagc atggttacaa 5100 atcagccaag ataacaaatt aatgagttgt aacgatacaa gcaaagcaaa tgccttatta 5160 gacatggtaa cgcaaggttt aaatccagct aaaaatcaat gctactttat tccttacggc 5220 aacaaaatgc agttacaacg tagctatcac ggtaatgtaa tgatgttaaa acgtgatgca 5280 ggtgctcaag atgttgttgc tcaagtgatt tataaaggcg atacattcaa gcaagaaatg 5340 ggaggaacag gacgtatcaa agcgattaaa cacgaacaag acttctttaa catcgacaaa 5400 gaaaacatta tcggtgcgta ctgcacaatc gtatttaatg atggacgaga taactatatt 5460 gaagtcatga ctattgaaca aattaaacaa gcatggatgc agtcatcaat gattaaagat 5520 gaaaaagcat tacaaaattc taaaacacat aataatttca aagaagaaat ggctaaaaaa 5580 acagttatca atagagctgc taaacgttat atcaacacat caacagatag caatcttttc 5640 aaatacgcac aagaatccga acaacgtcaa cgcaaagaag tgttggacgc agaagttgaa 5700 gaaaatgcaa atcaagaaca attggacttt gaacaaccag ttctcgaaga agcacaatac 5760 acagaattag aaaatgataa gcctattgat gtatctgact ttgaagaaat aaaagaacct 5820 gcaacagaaa aagaaagcga agaagagcca ttttaattga aacaatagca actggttcaa 5880 gtggtaactg ctacgtctta aatgatggac gtactacgtt actacttgag tcaggtataa 5940 aatttgaacg tgttcaaaag cattttaaat ataaaacaag acatatagca gggtgtctta 6000 tcacacacga acatggtgat catgcaaagt acacaaagca gtttgtcgac aatggtgtaa 6060 tcagctatat gactgctgga acacaacaag ctatgaattt tgaaagtcat cgcttatgca 6120 cgattaaggc aaagcaagag ctgcgaatag gcacatggtc aattctaccg tttgacatcg 6180 aacatgatgc taacgagcct gtggctttct tattacaaag tacattaggt tataaggttc 6240 tgtatgttac tgatacaaag tatttgaaat acaaatttaa cggcattacg cacatgatgt 6300 tagaagttaa ttatatctat gaacaaatgc aggaaaacat aaaaaacggc agtgtgcaca 6360 gcacattagc aaacagaatt atggagtctc attttagctt agaacatgct atcggaatgt 6420 taaaagcaaa tgatttaact agactcgaag aaatacattt aattcattta agtagtcaaa 6480 attcaaatgc aaaatacatt aaaagtgaaa tacaaaaagt gacgggcgcg cccgtttatg 6540 ttggaggttt ataaatgcta aacagaacaa tattagttgg tcgtttaact agagacccag 6600 aattaagaac cactcaaagt ggtgtaaatg tagcatcatt cacattagca gttaaccgca 6660 catttacgaa tgcacaagga gagcgcgagg cagactttat taatatcatc gtatttaaaa 6720 aacaagcaga gaacgttaat aaatacctat ctaaaggatc gttgacgggc gtagatggta 6780 ggttacaaac gcggaattat gaaaataagg aaggtcaacg tgtatatgtt acggaagtta 6840 ttgctgatag tattcaattt ttagaaccga aaaactcaaa tgacactcaa caagatttat 6900 accaacaaca agtacaacaa acacgtggac aatcgcaata ttcaaataac aaaccagtaa 6960 aagataatcc gtttgcgaat gcaaatggtc cgattgaaat agatgacaat gatttaccat 7020 tctaatttaa ccggtttgaa agtgaggtgt gtatatgact ggttggataa gtattgatcg 7080 ctcaattcaa aatcattggc tatttaaaga aaagagaaca ttttcaaagt ttgaagcatg 7140 gatatattta ctcatggaag cgaatcattc aaaggcaaaa gtgcctattg gaaaccaaat 7200 tgtaaccgta gaaagaggac aaagattaac atcgattttg accttgtctg acctttttaa 7260 ctggtcacga tttaaagtga aaaccttcct tgacttactc gagagtgatg gaatgttaga 7320 agtcaaaaca acatcaaaat atacccttat aaccattgtc aattatgact tttatcaaag 7380 tgagcaggga aggaaccaac atcaaaacga catcaaacca acatcaaaac aacatcagtc 7440 aaacatcaat ccaacatcaa aacaacatca aaccaacaca aacaataatg ataataaaga 7500 taataatgaa aagaatgtga ataatgagaa gaagaaggca gctgccttcg acttcttcca 7560 agataacgga ttcggtttca taactcctta caatttagac gatttaaatt actatcttga 7620 ttcatttgaa aatgattcag atcaaatagt taccgcatca cttaaaatcg ctaaagacag 7680 aaataaagtt acttggggat atgctaaaag cattttgaat acatggctta atgcaaactt 7740 gaaatctatt gaacaagtac gtgcatttga aaagcaacaa ctggaaagca aaaagcaaac 7800 taataaacct tatgttaaac catcgaaaga aaaaacaccc aaatggctca cagacagcac 7860 gagagaaacg aaaacgccgg aagtagatga aaaccttgag aaagacagag aagcttttat 7920 taagcgtcta aatagcaaat gggagtgatt gaaaatggat gcatttgata aatactatct 7980 atttgatcat gacggcaaca aaatgttttc agttacacca cattttaaag atggtcggca 8040 tttagttgtt ggaataaaag aaacaaaatt taatggtcgt cgttggtatt tagacgatta 8100 tgaattaaat acacttattg ataatgaaca aatggagtta ggacaccaaa caagcttatt 8160 tgaatatata tgagggatta catggagata gaaattaaat ttaatgaagt gtttaatgcg 8220 ccgatggggt cgccccgtcc acgctttcgt aaaacaggta gatttgttca aacttacatg 8280 ccaacgtctt acacaaagca taaagcgtat atacaagggc aaatgcctaa gttaaatcta 8340 gagcgcgcac taaaaatcga attagacttt tactttccat tgcttaaatc gtggtcgaag 8400 aaaaagaaaa gcgaaatggt tgggcagtat aaagtgacta agccggatat cgacaactta 8460 attaaaacgg tattagatgc ttgtaatggc catgtatgga aagacgataa ccaaattaca 8520 gaaataacta gctcaaagcg ttatggaatt gagcccaaaa taatcatacg aatagaagaa 8580 atataagagg tggataaaat ggcgagaaaa gcaagaattg taacaataaa cgataaacct 8640 tataggttca gtaaatttga aatggaatta atagaaagtc acggtataac cgctggaatg 8700 gtttctaaga gagtaaaaga cggttgggaa ctacatgaag caatggacgc accagaaggt 8760 acgcgtttaa gcgagtacag agaaaagaaa acaatagaaa gactggaaca agctagactc 8820 gaacgcaaat tggaaagaaa gcaaaagaaa gaggctgagc taagaagaaa gaagccacat 8880 ttgtttaatg taccacagaa acatccaaga ggacgttatg cgtgctacct gatggaaaac 8940 gacatattcg tgaaagttaa gaagtagatc atgacagata acgcacgcaa agaataccta 9000 aatcaattct ttggatctaa gagatatctg tatcaggata acgaacgagt ggcacatatt 9060 catgtagtaa acggcactta ttactttcat gggcatatcg taccaggttg gcaaggcgtt 9120 aaaaagatgt ttgatacagc agaagagctc gaaacatata taaagcaaca tggtttggaa 9180 tacgaggaac agaagcaact aactttattt tagaggagat ataaaaatga aaatcaaatt 9240 taaaaaagaa atgacattag atgaattaat taagtgggca tgggagaacc ctgaattagt 9300 aagaggagag aaattttatg cgcaaggcaa gagtaatgaa acatatgtgt atttccatct 9360 ttacgacgga agaaagtgca tcttaagaga atatatatca gccgatgaca cttttgaagt 9420 cgaatatgaa gaggaaatca cggaagaaac tgtaataccg aagttagtaa aaatgtacaa 9480 agacggaaaa atgtccgttt acaatgacta ttcgattaag cgttctttgc tttattcccc 9540 taaagcatac tatatcttaa acgacgacct aactatgacg ttaatctgga aagatgggga 9600 gttggtagaa tgatgcaaac ctataaagta agtctttgta tcaagttctt agcgtctaaa 9660 tgtaattata aattaaaaaa gcattatttt gtgcaaagta cgaatgagga agaagccacg 9720 aatacggtat taaaactgac tcgtaaaaag ctcccgttcc aaactgcaag catagaggtc 9780 gaaaaagtgg aggtagtagt atgatgccga aatatcgagt gtgggacgaa tatacaggaa 9840 gaatacacga tgttgtagga ttcgacttca ttgagactga agttcactat gaaaactacg 9900 cggaagcaga agctttaata catgcaagag attttaaaga tgtagaactt atgcaaagta 9960 caggacttaa agacaaaaac aacaacgaaa tatatgcggg agatatagtt gagtttgaag 10020 atgaaatatt agagatgcca gacgatgaat ctgtaatagg aacaattaat agagcagtaa 10080 tatctattga tgttgtaaat ggtattcaat taaaagattt tatgtttgag ggcgcagtct 10140 ccgaaaatga ttactttgag tatatagaca taaaatcctt ccttagatat gactgtgagg 10200 ttaaaggcaa catatttgaa tcatcacatt tattggaggt aacagaatga actatgaaac 10260 aggggtccaa ctaggtgtaa tggacgctag gttgaagaag atgagaaaac aacgtgatga 10320 gtacaagaag caacgtgatg agcttattgg ggatataggt aagttaagag aacgcaacaa 10380 agagctggag aagaaagcaa gtgcatggga taggtattgc aagagcgttg aaaaagattt 10440 aataaacgaa tttggcaaag atggtgaaag agttaaattt ggaatggaat taaacaataa 10500 aacttttatg gaggaagaca ctaatgaata accgtgaaca aatagaacaa tccgttataa 10560 gtgctagtgc gtataacggc aatgacacag agggattact aaaagagatt gaggacgtat 10620 ataagaaagc gcaagcgttt gatgaaatac ttgagggaat gacaaatgct attcaacatt 10680 cagttaaaga aggtattgaa cttgatgaag cagtagggat tatgacgggt caagttgtct 10740 ataaatatga ggaggcacag gaaaatgact aacacattaa caattgatca gttacaagag 10800 ttattacaaa tacaaaagga gttcgacgat agaataccaa cgctgaactt acgagatagc 10860 aaaatagcat atgtagttga attctttgaa tggtttaata cattggaaac gtttaagaac 10920 tggaagaaga aaccaggtaa gccgttagac gtacaacttg atgaattagc tgacatgttg 10980 gcgtttggat tgagtattgc gaatcaagta ggagtgtcat cagaagagat aaaagaagcg 11040 attgaatcaa gttttaaaga tacagaattt cacaaaatgt ttaattttaa agataaagaa 11100 tttgctcaag acgcagttgt tagtacacca cagataatat tcaaagaatt ttatcccgac 11160 caacaagcaa ttgttatagt gatagacata gcttacaact tatattctat cgaccaactc 11220 attgacgcat acaaaaagaa aatgaaaagg aatcatgaaa gacaagatgg aacagcagac 11280 gcaggaaaag gatacgtgta aagacatatt agatcgagtc aaggaggttt tggggaagtg 11340 acacaatacc tagtcacaac attcaaagat tcaacaggac gcaagcatac acacataact 11400 aaagctaaga gcaatcaaag gtttacagtt gttgaggcag agagtaaaga agaagcgaaa 11460 gagaggtacg aggcgcaagt taaaagaggt gcagttatta aagtgggtca gttgtttgaa 11520 aatataaggg agtgtgggaa atgattaagc aaatactaag attattattc ctactagcaa 11580 tgtacgagtt aggtaagtat gtaactgagc aagtatatat tatgatgacg gctaatgatg 11640 atgtagaggc gtcgagtgat tacgtctttc gagcggaggt gagtgaataa tgagaatatt 11700 tatttatgat ttgatcgttt tgctgtttgc tttcttaata tccatatata ttattgatga 11760 tggagtgata ataaatgcat taggaatttt tggtatgtat aaaattatag attccttttc 11820 agaaaatatt ataaagaggt agataaaaat gaacgagcaa ataataggaa gcatatatac 11880 tttagcagga ggtgttgtgc tttattcagt taaagagatt tttaggtatt ttacagattc 11940 taacttacaa cgtaaaaaaa tcaatttaga acaaatatat ccgatatatt tagattgttt 12000 taaaaaggct aaaaagatga ttggagctta tattattcca acagaacagc atgaattttt 12060 agattttttt gatattgaag tctttaataa tttagataag caaagtaaaa aagcgtatga 12120 aaatgttatt ggatttagac aaatgattaa tttatcaaat agagttaagg caatggaaga 12180 ttttaagatg agtttcaaca atgaatttag tacaaatcag atttttttta atccttcttt 12240 tgttatggaa acaattgcta ttataaatga atatcaaaaa gatatatctt atttaaaaaa 12300 tataattaat aaaatgaatg aaaatagagc ttataatcat attgatagtt ttatcacttc 12360 agagtaccga cgaaaaataa acgattataa tctttatctt gataaatttg aagaacagtt 12420 tagtcaaaag tttaaaataa acagaacttc gataaaagaa agaattatta ttaatttaaa 12480 caagaggaga tttaaatgat gtggattact atgactattg tatttgctat attgctatta 12540 gtttgtatca gtattaatag tgatcgtgca agagagatac aagcactcag atatatgaat 12600 gattatctac ttgatgaagt agttaaaact aaaggataca acgggttaga agaatacagg 12660 attgaattga agcgaatgaa taacgatatt aaaaagtaat ttatattatc ggaggtattg 12720 catgtataac aggaaagaaa tacgtgaaat gatagataac tacaagtgga tgaagaacat 12780 aatagacagt aaagtctacg ataacgaaag tacatcaatt gcacaatatg gttatcaatc 12840 tgcgatgcca aaagctaaag gcacgactag caataaagtg ttagtgaaag ttataaacaa 12900 aaacaaagcg cttagaaagt acgattactt gattaagaag atagcgttca ttgatgaata 12960 tgaagaatac atcacgaatg aaaaagatta tcatatttta caaatgttaa aacaacgaga 13020 aagccataat aggattatga gtattcttga tataggcaga gacaattttt attctagagt 13080 aaaagatata gtaaatatac tttataactt gcaacaagaa accgacacat cgtacacatc 13140 ggacagttcg gacacatcgt acaaatcgta cacatcggac taattttgat gctacatatt 13200 gttttttatt ataattgcta tgtagcaaaa catttatatt tattttgaac tctcacatta 13260 agtgagggtt tttattttta taaacaagag gtggagaatg gagatatcaa agtaccaaga 13320 gatagctaca cgtacacaca atgatgaatt gaatttaaat gaatctatta cttgttacgg 13380 cttaggttta actcaatcta cagacaatgt tacagatcta attaaacagc atatgttttg 13440 taatgtaccg atagataaag gaattatgat aaatgaactt agcgaagcat tgtggaatat 13500 agctaatctt actaacgtgt taggtattaa cttggatgag atagctggtc atagtgttaa 13560 cactatcttg atgaataaac ctaatcagac tatcaattta gacaatggta taaaacaagg 13620 agacaaagta ttgtttcaag gtagtaagta tcttgttgat ggatcgatag gaaacttatt 13680 gttaattagc aatgataaag atgatagaca agtaactgtg caagatgtta agaaagtcga 13740 caaggagtga tgtgcattgt ctattatgaa gcgatgtggt catccaacat gtaatgtatt 13800 gattaatcat aatgaaagtt attgtgataa acacaagcaa tatgcaaatg aaaattacaa 13860 tgatttgaga cgtcgaaacg atccagagta tttaagattt tataaatcga aaacgtggca 13920 aaacatgcgt cgaattgtat tgttagaaca tgattttatt tgtgtttctt gtggcaatca 13980 agcgactatg gttgaccata ttgtaccaac aaaaattgat tgggcaagaa gattagacaa 14040 aagtaattta cagcctttgt gtgatgcttg ccataaccaa aagacaaaag aagatttgaa 14100 gaaatattaa aaaagataaa aataggaagt ccccccaaag atgaaacggg cgtcaatgaa 14160 aggttctgga gaacggagca gagttttctt ctcaaaaaat tccctttatt taagtttttt 14220 tagtaggagg tgctaattta tggcgggtag acctaagaag cttttgtcaa attcgaacaa 14280 gaattataca aaagaagaaa ttattgaaaa agagcgtcaa gaagctcaat taaataaatt 14340 ttctaaaatc gatactgaac caccgcactt tttagatgaa atagcgaaac aagaatactt 14400 aagaatatta ccgcacatgc aagaattgcc aatttccaac ttagataaag cacaattagc 14460 acaatattgt agtttttata gtgactttgt taaagcaagt ttgattttag agcgcgaaga 14520 cttgatttta gaagacgaca aaggaaatca aaaggttaat ccggcgttca acataaagga 14580 aaaagcgggt attcgattgc aacaaacagc taatacttta ggattaacta ttgatagccg 14640 attgcgtatt atggttcctg atgaaaaaga agatgatgat ccatatatgg aatttgtgag 14700 tgattagtaa tgactgatta tgttactaaa tacgcaaaaa aggtagtttc aggagaaatt 14760 ttggcaagtt tgaagaatat tcaagtatgt aaacgtcacc tatcttttat ggagaacccg 14820 ccgaatggtt gccattggga taatcatttg tctaacaaag caattaaatt tgtggaaatg 14880 cttccagacc ctaaaacaaa ccagcccatg cctcttatgg agtttcagaa attcattgtt 14940 gggagcttat acggctggcg tagaggtcaa tacagaatgt ttactaaagc ttatataagt 15000 atggctagaa aacaaggtaa gtctctaatc gtatcgggaa tgtccgttaa cgaactgttg 15060 tttggacaat accctaaatt taatagacaa atttatgtag cttcatctac ttataagcaa 15120 gcgcaaacaa tattcaagat ggcaagccaa caagtaaacc taatgcgaag taaaagcaag 15180 tttatccgtg aaaaaacaga cgtaagaaag acagacattg aagatgtatt aagtagttca 15240 gtgtttgcac ctctttccaa taacccagat gcggttgatg gtaaagatcc tacagttgtt 15300 attttggacg aattggcaag tatgcctgat gatgagatgt actcaaggtt taaaacaggt 15360 atgacattac aaaaaaatcc tttaacccta cttgtttcaa cggccggaga caatttaaat 15420 agtcaaatgt accaagagta taagtatatt aaacgtattt taaatgaaga agtaagagct 15480 gataattact ttgtatattg tgctgaaatg gattcacaag aagaagttca agatgaaaca 15540 aagtggatta aagcaatgcc gcttttagaa tcaaaagaac atagaaaaac tatacttcaa 15600 aatgtaaaag ctgatataca agacgaatta gaaaaaggga catcatatca taagattttg 15660 attaaaaact tcaatttatg gcaagcgcaa agagaagata gcttgctaga tatttcagat 15720 tgggaacaag taataacgcc tatgcctaat atcaatggta aagatgtgta tataggtgtc 15780 gacttatcga gattggatga cttaacatct gtagggttta ttttccctaa cgacgataaa 15840 aaagtgtttt tacatagtca ttctttcatt ggattaagaa caaacttaga acaaaaatct 15900 aagagagaca aaataaatta tgaattagcg attgaacgtg gcgaagctga gactacacaa 15960 tcagatagcg gcatgattga ttataaacaa gttatcgatt ttatagtgaa atttataacg 16020 acgcatgacc tgaatgtaca ggctgtttgc tatgaccctt ggaatgcgca aagttttata 16080 acaacaatcg aatcaatggc tttagattgg ccactcattg aagtgggaca aagttttaag 16140 gcgttatcac aatctattaa agaatttaga atgtgggttg cagatgaaag aatacagcat 16200 aacgataata tgttacttac aacatcagtt aataatgccg ttttgattcg tgacggagaa 16260 gacaatgtga aaataaataa aaaaatgaat cgtcaaaaaa tagatccgat tatttcgatt 16320 atcacagctt tcactgaagc tagaatgcac gaattccaag aaaattggac ggagaaatat 16380 gaaagcgaag aattcggatt ttaaaggtgg tgacaaaatg gacttgaata aaataaatgt 16440 cttttttaat ttcttggttg ctaatttggt tagcatcctt tttttattag gtttgtttgt 16500 ggttaatgtt tctgtgtata aagcattcgg tcaaaatata ggacttttat gcattggtat 16560 aacactgatt gttgtttcgt tgattttaaa tcatgaaagc aatcaagaaa ggagttagta 16620 gttgtgggga ttttttataa aaatgaaaaa cgagacttgc aatacaacga agatgatttg 16680 caaatgatgg ttcaaacttt gccaggtttt caaggaacaa aattacgaca atataaagat 16740 atagaagcaa ttaggcatag cgacatcttt actgcagtta tgatgattgc ttctgatttg 16800 gcgcgcatgc caattagggt gacagtgaac ggccaaatta attatagtga caggattgtt 16860 aatttgttaa atacacgtcc taacccaatg tataacggct atatattcaa attagtagtg 16920 tttgttagtg ccttactaac atcgcacggc tatattgaaa ttacacgtga taaaacagga 16980 gaacctatga atttaacgtt cagaaagaca tccgaaatag aattgaaatc agacgcaaga 17040 ggtcgactgt attattttca tcaaaggata gacagtaacg gaaataatat agaacgtaat 17100 gttaagtttg aggatatgct agacatcaaa ttttattcgt tggatggtat aaatggtttg 17160 tcactgttag acacattaag tcgcacgata gaatcagata acaatggaaa agatttcctt 17220 aataatttct tgcgaaatgg cacacatgct ggtggtattt tgaaaatgaa aggtgtatta 17280 gataataaaa aagcaagaga ccgtgccaga gaagaatttc acaaaagttt tagtggaact 17340 aaacaagctg ggaaagttgt cgtactcgat gaatcaatga cgtttgatca attagaagtt 17400 gatacagaag ttttaaagct tatcagagaa aacaaatcat caacaagaga aatagcaggt 17460 gtatttggta ttccattgca taagttcggc atagaaacag cgaacatgag tatcacggat 17520 gctaatttag attacttatc aactttaaaa ccttatatta catgcgtttg tgcagaattg 17580 aattttaagt ttaatgatga atatgtgaat cgtgaattta aatttgatac cactgaaata 17640 cgagttgttg atgaaaaaac acaagctgaa attgacaaaa ttaacattga ttctggaaag 17700 atgaatatcg atgaaattag acaacgtgat ggattagcgc caatatcagg cggtaatggt 17760 agcattcaca gagtcgattt aaaccatgta aatattgaac ttgtagatga gtatcagatg 17820 aataaatcga gagctactga taaaaaattg aaaggtggtg aggaaaatga gtaaggaaac 17880 gagagttggc aacattattg aggtacgctc aaatgataac aacgaaatgg tcatagaggg 17940 gtatgcgtta aagtttgaca cttggtctga aaatcttggt ggattcaaag aaacgatttc 18000 acgtcgcgct ttagaaaaca ctgatttatc tgatgtgcgt tgtttagtag atcatatccc 18060 atcgcaaata attggtagga caaaatcggg tactttggag ctcgaaactg atgatgttgg 18120 acttaaatat cgttgtaagt taccaaacac aacatttgca cgtgatttat atgagaacat 18180 gcgtgtaggc aacatcaatc aatgttcgtt tggttttatg cttgacgata aaggcgatga 18240 agtgcgtttt gatgaacaag aaaacattta caaacgtact ttaacagcaa ttcgtgaact 18300 tacagatgtt tctgtagtga cttatccggc ttacaaagac actgatgtta aaccagcatt 18360 acgtagtatt gaaaccgtta aaaaagaaca acgtaaaaaa gaattagaaa taagactaaa 18420 gaaacactct atattaaata atatttggtg aagttgaaca ccattatcaa atacagccat 18480 tggacatgct gaatatagcg atgtctattt ttttatgcca attttaggag gaaattaaat 18540 gaaaacaaaa gaagagttac aatctgagat ttcagacatt aaaagacaaa ttgatttaaa 18600 ggtgaagtat gcaacgagag cacttaataa cgatgagtta gaaaaagcag aaaaattaga 18660 acaagaaatt actgatttac gttctcaaat ccaagaaaaa caagaagaat tagataagct 18720 aaaagaaaaa gatggaactt cagaaaacaa tcaacaatca gtggaagtaa acgaagcacg 18780 tacttatcga aaccaagcaa acattaatga tttaggtatt tcgattcaaa acacaaaggt 18840 aacatcacaa gaagttagag attttactga atatcttgaa acacgcaatg atattcaagg 18900 tggttcgtta aaaacagact caggatttgt agttattcca gaggaaattg ttacagatat 18960 tttaaaatta aaagaggttg agtttaatct tgataagtat gtgacggtca aacgtgttac 19020 aaatggttct ggtaaatatc cggtagtacg acaatcagaa gttgcagccc ttgaaaaagt 19080 tgaagaatta gaagaaaacc ctgaattagc agttaaacca ttcttccaat tagcatatga 19140 cattaataca caccgtggtt acttccgaat ttcacgtgaa gcaatcgaag atgcaaaagt 19200 gaatgttttg caagaattga aactatggat ggcgcgaact attgcagcaa cacgaaacaa 19260 agcaattatt gatgttatca ctaaaggatc aacgggttct acaagttcag gttttgaaaa 19320 agaaggcaag aaattagaag ttaaaaaagc aaaatcttta gatgatatta aagatgctat 19380 taacctgaat gttaagccaa attacgaaca taatgttgcg attgtttcgc aaactatgtt 19440 tgcaaaatta gacaaaatga aagataagct aggaaactat ttaatccagc cagatgttaa 19500 agaaaaaacg caacagcgtt tattaggagc taaaatcgaa attttacctg atgaagtact 19560 agggcaaaaa ggtaataaca ctttgattat cggtaactta aaagatgcga ttgttttatt 19620 tgaccgctct caataccaag catcatggac tgactacatg catttcggag aatgtttaat 19680 gattgctgta cgtcaagact gtagaattct agattataaa tcagcaattg tgattgaata 19740 tgatgatagt gaacgcggtg aaggcgatct tggcttagaa gcataataag cgctcgatac 19800 tttataaaga ggtgataaac tatggcaatg tatgaagtga agaaatctta tactgacttg 19860 gaaaaaggcc agtatttaaa gtcaggtaaa cgtgttgaaa tgacagtaaa acgtgctgaa 19920 tatgttaaca aaaagctgaa agagcatgga gtaatacttg aaagagtaaa agaagaatag 19980 gtgattgaat gcaattaaca gctgaggaac ttaagttatt aaaaaagcat tgcaaaatag 20040 atcacaattc agaggacgac ttattagaaa tatattactc ttgggcattc catgaaatag 20100 ctagcgctgt tacggatgaa ccaagtaaat atattgattg gtttaaaagt catcctctat 20160 ttgctcgtgc tatataccct ttagcaagtt actattttga aaaccgtatt gcttatttgg 20220 atagggattt atcgcttgcg ccacatatgg ttttaagtac ggtgcataaa ttgagaggtt 20280 catttgagca atttttggag agtgaaaatg atgaaattta attccaataa attaaatgaa 20340 cgtatagatt tttgtgaaga tgtaagcgag agagtgaacg gaaatccgat gaaaccgaag 20400 acgaaaatat tatactcttg tttcgcttgc attcaagaat ctaaagaatc cgacactcaa 20460 acgaatctca atacaggtag caaattcatt aaaactatta ttatcagaga tacacgaggt 20520 gattataaac caacaaataa gcattacgtc ttgcatgaag ggcaaagatt taacatcaaa 20580 tatgtaaagc cagattatca agataaatct tatttgcgta tctatggcga ggtggtcatt 20640 taatgggggc aagaattgaa agtaataaca tcgaacaagg tttgaaaaat gcagttttaa 20700 aaatgaattt aaatagtaat gtaattgtca aagctggggc tatgtcatta gtcccgcttt 20760 taaaaagtaa tacacctttt gcgaatacta aaaagcatgc tcgcgatcac atagctgttt 20820 ctaatgtgaa aacagacaga cacacaagtg agaaaatcgt tacaattggt tacgctaaag 20880 gcgtctcaca tcgtattcat gcaacagaat ttggaacaat gtaccaaaaa ccacaattgt 20940 ttataacaaa aacagaaaag caagggaaaa acaaagtttt aaaaacaatg cttgatactg 21000 ctaagaggtt gcaaaaatga ttaatgttac caaattaatt agaaacgcta ttattgcaaa 21060 taacattaca gatgaagtga atgtgtttaa ctacactata gatgaccatt ttcacgaaaa 21120 aactgacaag cctattattc gtatatatcc cttaccgttc aatcctgaca catacgctga 21180 tgataacgag atttcaagag aataccatta ccaaattgat gtttggtggt ctcaagatga 21240 accgaacgag caagcagaaa aaattgttga gttactcaaa gtgataaatt ttcaatgtta 21300 ttacagagaa ccgttatacg agagtgacgt catgtcattc agacatatta taagagcaaa 21360 aggctcgatt ttatcaatga aattggagga aaattaaatg attgaaaaat tgaaacaagc 21420 accaagattt ttaaaattaa acttacaaca ttttgcagat acaggagttt cgggtatcgc 21480 aattggggta tcaaactttt attatgcacc tattttaaaa gatacagaaa atgaatggga 21540 aactggagct ggcacacgta ttcgtttctt aaaagaaatt gaagtagacc gtccacaaga 21600 taccgaggaa gattatgggg atgatatggt cgcagcaact gctgtatcta atggtaaact 21660 aagtgttaag acaacatttg ttactgttcc tgctgacgat aaggcgttct tgaatggcgc 21720 taaaaaaggt gtaggtggtt ataaatatgg agctaaggat atcccgccag atgtagcgat 21780 tgtatttgaa agacgtaatc atgatgagtc ttcagaatgg gttggcttgt tcaaaggtaa 21840 attcactcgt tcaagcatca aagggcaaac aaaacaagat aaagttgaat tccagaatga 21900 cgacgtagaa ggcaatttta ttgatcgttt gtttgatgag agctcgcatg ttactggcta 21960 tgataaaaaa ggaagcacta cagggcgcga ttatgtattc atggaaacat ttggtaaaac 22020 ttatgatgaa ttcatgtcta gtcgaggaga acaaaatatg gaacctgtag aaaaagaaat 22080 gaaaaaaaca gaaaaagttg aagtcacttc tgtaaacgtc actgatgaac aagttacagt 22140 taaagttgat gctactaaac aactatcagc cacaaccgaa ccatctggac agaaagtaac 22200 ttatgcagtg actgaggggc aaacgtatgc tagcgtaaca tcaactggcc tcgttaaagg 22260 tttggcggaa ggtaatgcga ccgttacagc gactgcagga aagcaaactg atactgtgca 22320 aattacagta caatctaatt tagaaatgta agttttgagg gcttaacgcc ctctttttat 22380 tttggccaaa ttaaaaagaa agtaggaatt taataatgga acgtacatca attgaattaa 22440 ttacaggatt tacaaaaaca ggaaagccgc aatatcaaaa gtatttagcg aagccgatta 22500 ttactttgtt tgaaacaatt caaggttcaa aattaggttt gaaacttaac aaagccttta 22560 agggggctga ttttaaagat ctaacagaag aagaatttaa taacttaagt gtgacagaac 22620 aggaagaata caaaaacaag caagaagaat acgaaaacaa catggctgta caaatggaag 22680 tattagaaga agttttggat ttcatcgttg aagcttttga taatcaattt accagtatag 22740 aacttcaaaa aggattacca aatggtcaag aaggtattga aaagattgga cagttaattg 22800 gacgaattac aggtggggaa cctagcgata caaaaaagtt cgtgacagag aatcagaaat 22860 aagaaaagaa gatttaacac ctgaagctgt ctacaacaat tacaggaaaa tagctaaaga 22920 tttgatagaa aaaggcatgg atgcagaaaa agtggctaac atgccgatac acttcttttt 22980 agacattgtc gaatcgaaga ttgaaacaaa gcgaactgcg aaaagtttta aagatatttt 23040 ttaatcagcc tttaaaggtt gattttttat ttacatcttg gaagaaagga ggtttttaaa 23100 tgcctaatcc tataggtaat atggtcataa aggttgattt agatggttct ggattcaata 23160 gaggtgtgac aggtttaaat aggcaaatga aaatggtttc gcgtgagctt tcggctaatt 23220 tatcacaatt ttctagatat gataattcat tagaaaagtc gaagataaaa gtcgaaggtt 23280 tgagtaaaaa acaaaaagtt caagcccaga ttactaaaga gctgaaagat agttatgaca 23340 aacttagtaa agaaactggt gaaaacagtg caaagacaca agctgcggct gctaaataca 23400 atgaagctta cgctaaatta aaccaatatg agcgagagtt aaaccaagcc acacaagaat 23460 taaaagacat gcaaagagag cagaaagcat taaatactgc aatgggaaaa cttggtacca 23520 actttaataa ttttggtcct aaacttcaag aaattggtaa cagtatgaaa aatgtaggcc 23580 gtaacatgac tatgtatgta actgcgccgg tggttgctgg gtttgctgta gcagctaaaa 23640 aaggtattga attcgatgac agtatgagaa aagttaaagc aacttcaggt gctactgggg 23700 aagagtttga agctttgaag aaaaaggctc gcgaaatggg tgcaacaaca aaatttagtg 23760 catcagattc ggctgaagca ttaaattaca tggcacttgc tggttgggat tctaagcaaa 23820 tgatggaagg tttaagcgga gttatggatt tagcggcagc atctggcgaa gaactgggag 23880 cagtaagtga cattgttaca gatggactaa cggcatttgg tttaaaagca aaggatagtg 23940 gtcattttgc ggacgtttta gcacaaacta gctcgaaggc aaatacggat gttagagggc 24000 tcggagaagc ttttaaatat gtcgctcctg tagcaggtgc gttaggttac acgattgaag 24060 atacatctat tgcgataggt ttaatgagta atgctggtat caaaggtgaa aaagcaggta 24120 cagcgttacg aacaatgttc accaatcttt caagtccaac tagagctatg gggaatgaaa 24180 tggaacgctt aggaatatct attacagata gtaatgggaa aatgattcct atgcgaaagc 24240 ttttagacca actgagggaa aaatttaaac atctttcaaa agaccaacaa gctagttctg 24300 cagctacaat atttggtaaa gaagcgatgt caggagcatt agcgattata aatgcttctg 24360 atgaagacta tcaaaagtta accaaatcta tagattcatc taccggcgca tctaaaagaa 24420 tggccgatac aatggaatct ggtttaggtg ggaaattaag aactttaagg tcgcaattag 24480 aagaactagc cctaacgatt tatgacagaa tagaactagc actaaagatt atagtaagtg 24540 cttttagcaa agtagtgaca tgggttacta aattaccaac gtcaattcaa ttagcggttg 24600 ttgggtttgg attatttgta gcagttttag gtcctttagt ttttatgttc ggtttattta 24660 tcagcgtgat ggggaatgca atgacagttt taggaccctt gttaataaac gttaataaag 24720 ctagtggttt attcgcgttt ttaagaacta aaatcgcatc acttgttaaa ctatttccga 24780 ttttaggtgt gtcgatatca agtttaacgt tgcctataac attaattgta ggtgcattag 24840 ttggtattgg catagctttc tatcaagctt ataaacgttc agaaactttt agaaatattg 24900 taaatcaggc aatctctggt gtagcaaacg catttaaagc agctaaacta gcgttacaag 24960 gtttctttga tttattcaaa ggtgatagta aaggcgcggt taccctagag aagatatttc 25020 cacccgaaac tgtagcagga atacaaaatg tagttaatac gattagaaca actttcttta 25080 aagtagttga tgcaatcgtt ggtttcgcca aagagatagg cgctcaatta gcctctttct 25140 ggaaagagaa cggctcagaa ataacacaag ctttgcaaaa tatagctggt ttcattaaag 25200 caacctttga atttattttt aactttatta ttaaaccaat catgtttgcg atttggcaag 25260 tgatgcaatt tatttggccg gcggttaaag ctttgattgt cagcacttgg gaaaatatca 25320 aaggtgtaat acaaggggct attaatatta ttttgggtat tatcaaagtg ttctctagtc 25380 ttttcacagg aaactggcga ggcgtttggg acggcattgt aatgatactg aaaggtactg 25440 tgcagttaat ttggaattta atacaactgt ggtttatagg taaaattcta ggtgtagtga 25500 gatactttgg tggattactt aaaggtttaa taactattat atgggttgct ataataggcg 25560 ttttcaagaa atcattatcg gcaatttgga atgcaacaaa aagtattttt ggtttcttat 25620 tcaatagtgt taaatctatt ttcactaata tgaaaaactg gttatctagt acgtggaata 25680 atatcaaaag caataccgtc ggcaaggctc attcgttatt tacgggtgta aggtctaaat 25740 tcacaagttt atggaatgcg acgaaagata tatttactaa attaagaaat tggatgtcaa 25800 acatctggaa ctctattaaa gataacactg taggtatagc tggtcgctta tgggatagag 25860 tgcgtaacat ctttggaagc atgcgtgacg gtttaaaatc tatcattggt aaaattaaag 25920 atcatatcgg tggtatggta gacgctgtta aaagaggtct taataaatta attgaaggtt 25980 taaactgggt cggtggtaag ttgggtatgg acaaaatacc gaagttacac actggtactg 26040 aacatacgca tactactaca agattagtta agaacggtaa gattgcgcgg gatacgttcg 26100 ctacggttgg ggataaagga cgtggaaatg gtccgaatgg tttcagaaat gaaatgattg 26160 aattccctaa tggcaaacgg gtacttacgc ctaatacaga tacgacagcg tacttaccta 26220 aaggttcaaa agtatataac ggcgcacaaa cttattcaat gttaaatgga acgcttccaa 26280 gatttagcat aggtactatg tggaaagata ttaaatccgg tgcatcatcg gcatttaact 26340 ggacaaaaga tcaaataggt aaaggtacaa agtggcttgg cgataaagtt ggtgatgtca 26400 tggactttat cgataatcca ggcaaacttt taaattatgt acttcaagcg tttggagttg 26460 atttcagttc tctaactaaa ggtatgggta ttgctggcga tataacaaaa gctgcatggt 26520 ctaagattaa gaaaagtgca atcaagtggc ttgaggatgc tttcgcagag tcgggtgatg 26580 gcggtgtatt agatatgaat aaattacgtt acttatacgg tcacactgct gcttatacac 26640 gagaaaccgg acgcccattc catgaaggtc tggattttga ttacatttac gaacctgttc 26700 catcaaccat taatggtaga gcacaagtta tgccttttca taatggtggt tatggaaaat 26760 gggtgaaaat tgtaaagggc gccttagaag ttatttatgc acatttatct aaatataaag 26820 ttaaaactgg tcaacaagtt agggtcggcc agactgttgg tatatcgggg aatacggggt 26880 ttagtacagg acctcactta cattatgaga tgcgttggaa tggaagacat agagacccgt 26940 taccgtggtt aagaaagaat aatgggggcg gcaaaagtac acccggtggt aatggtgcag 27000 ctaatgctag acgagctatt aaggctgctc aaaatatttt aggaggaagg tataaggcga 27060 gttggattac taacgagatg atgcgtgttg cgagtcgtga atccaattat acagctaatg 27120 cagtcaataa ttgggatagc aacgcaagag ctggtatacc ttcaagaggt atgttccaaa 27180 tgatagatcc ttcatttaga gcgtacgcaa agtcgggtta caataatcct ctcaacccaa 27240 ctcatcaagc tatatcggct atgagatata ttgtgggtaa atgggtacca agaacaggct 27300 catggagagc tgcgttcaaa cgcgctggtg attacgcata tgctactggt ggcaaagtct 27360 ataacggatt gtaccactta ggggaagaag gatatccaga gtggataata cctactgatc 27420 caagtagagc gaacgaagca cacaaattat tagctttagc tgctaacgat attgataacc 27480 gctctaaaaa taagcgacca aacaacttac caaatccaag tataagtaat agtgatacaa 27540 actatattca tacattggag aataaactgg atgcggttat taattgtttg gttagtttgg 27600 ttgagtctaa tcaagttatt gcagataagg attacgaacc agttattaat aagtatgtgt 27660 ttgaagatga ggtaaataat tctatcgata aacgagagcg tcacgaatct acaagagtta 27720 gatttagaag aggaggcacg ataatctaat gcaagataca attcaaatag acaataaaac 27780 cattgaatgg ttagttgtac aaagagggtt tgagataccc tcttttaatt ttgttactga 27840 aaaagaaagt gtgaaaggta gaacaggttc tattgctaaa gctcgttatc taaatgatat 27900 cgaatttgaa ttacctctaa taattagaaa tgaagtcttg gcgccaggtg gacaaaaaac 27960 gcatgacgat atattggaag agttagttga attttttgat attgacaatt taaagccgaa 28020 aaaacttaaa ttcaaatctc aaaactggta ttggtttgca tactttgatg gaccattaaa 28080 attaccgaaa aacccaagag gttcagtgaa gttcactatc aaagtagtac taacagaccc 28140 ttacaaatat tcagtaacag gaaataaaaa tactgcgatt tcagaccaag tttcagttgt 28200 aaatagtggg actgctgaca ctcctttaat tgttgaagcc cgagcaatta aaccatctag 28260 ttactttatg atcactaaaa atgatgaaga ttattttatg gttggtgatg atgaggtaac 28320 caaagaagtt aaggattaca tgcctcctgt ttatcatagt gagtttcgtg atttcaaagg 28380 ttggactaag atgattactg aagatattcc aagtaatgat ttaggtggta aggtcggcgg 28440 tgactttgtg atatccaatc ttggcgaagg atataaagca actaattttc ctgatgcaaa 28500 aggttgggtt ggtgctggca cgaaacgagg gctccctaaa gcgatgacag attttcaaat 28560 tacctataaa tgtattgttg aacaaaaagg taaaggtgcc ggaagaacag cacaacatat 28620 ttatgatagt gatggtaagt tacttgcttc tattggttat gaaaataaat atcatgatag 28680 aaaaatagga catattgttg ttacgttgta taaccaaaaa ggagacccca aaaagatata 28740 cgactatcag aataaaccga taatgtataa cttggacaga atcgttgttt atatgcggct 28800 cagaagagta ggtaataaat tttctattaa aacttggaaa tttgatcaca ttaaagaccc 28860 agatagacgt aaacctattg atatggatga gaaagagtgg atagatggcg gtaagtttta 28920 tcagcgtcca gcttctatca tagctatcta tagtgcgaag tataacggtt ataagtggat 28980 ggagatgaat ggattaggtt cattcaatac ggagattcta ccgaaaccga aaggcgcaag 29040 ggatgtcatt atacaaaaag gtgatttagt gaaaatagat atgcaagcaa aaagtgttgt 29100 catcaatgag gaaccaatgt tgagcgagaa atcgtttgga agtaattatt tcaatgttga 29160 ttctgggtac agtgaattaa tcatacaacc tgaaaacgtc tttgatacga cggttaaatg 29220 gcaagataga tatttataga aaggagatga gagtgtgata catgttttag attttaacga 29280 caagattata gatttccttt ctactgatga cccttcctta gttagagcga ttcataaacg 29340 taatgttaat gacaattcag aaatgcttga actgctcata tcatcagaaa gagctgaaaa 29400 gttccgtgaa cgacatcgtg ttattataag ggattcaaac aaacaatggc gtgaatttat 29460 tattaactgg gttcaagata cgatggacgg ctacacagag atagaatgta tagcgtctta 29520 tcttgctgat ataacaacag ctaaaccgta tgcaccaggc aaatttgaga aaaagataac 29580 ttcagaagca ttgaaagatg tgttgagtga tacaggttgg gaagtttctg aacaaaccga 29640 atacgatggc ttacgtacta cgtcatggac ttcttatcaa actagatatg aagttttaaa 29700 gcaattatgt acaacctata aaatggtatt ggatttttat atagagctta gttctaatac 29760 cgtcaaaggt agatatgtgg tactcaaaaa gaaaaacagc ttattcaaag gtaaagaaat 29820 tgagtatggt aaagatttgg ttgggttaac taggaagatt gatatgtcag aaatcaaaac 29880 agcattaatt gctgtgggac ccgaaaacga caaaggaaag cgtttagagt tagttgtgac 29940 agatgacgaa gcacaaagtc aattcaactt acctacccgt tatatttggg gaatatacga 30000 acctcaatca gatgatcaaa atatgaatga aacacggttg cgttctttag ccaaaacaga 30060 gttaaataaa cgtaagtcgg cagttatgtc atatgagatt acttctactg atttggaagt 30120 tacgtatccg cacgagatta tatcaattgg tgatacagtc agagtaaaac atagagattt 30180 taacccgcca ttgtatgtag aggcagaagt tattgccgaa gaatataaca taatttcaga 30240 aaatagcaca tatacattcg gtcaacctaa agagttcaaa gaatcagaat tacgagaaga 30300 gtttaacaag cgattgaaca taatacatca aaagttaaac gataatatta gcaatatcaa 30360 cactatagta aaagatgttg tagatagtga attagaatac tttgaacgca aaatacacaa 30420 aagtgataca ccgccagaaa atccagtcaa tgatatgctt tggtatgata caagtaaccc 30480 tgatgttgct gtcttgcgta gatattggaa tggtcgatgg attgaagaaa caccaaatga 30540 tgttgaaaaa ttaggtggta taacaagaga gaaagcgcta ttcagtgaat taaacaatat 30600 atttattaat ttatctatac aacacgctag tcttttgtca gaagctacag aattactgaa 30660 tagcgagtac ttagtagata atgatttgaa agcggactta caagcaagtt tagacgctgt 30720 gattgatgtt tataatcaaa ttaaaaataa tttagaatct atgacacccg aaactgcaac 30780 gattggtcgg ttggtagata caaaaacttt atttcttgag tatagaaaga aattacaaga 30840 tgtttataca gatgtagaag atgtcaaaat cgccatttca gatagattta aattattaca 30900 gtcacaatac actgatgaaa aatataaaga agcgttggaa ataatagcaa caaaatttgg 30960 tttaacggtg aatgaagatt tgcagttagt cggagaacct aatgttgtta aatcagctat 31020 tgaagcagct agagaatcca caaaagaaca attacgtgac tatgtaaaaa catcggacta 31080 taaaacagac aaagacggta ttgttgaacg tttagatact gctgaagctg agagaacgac 31140 tttaaaaggt gaaatcaaag ataaagttac gttaaacgaa tatcgaaacg gattggaaga 31200 acaaaaacaa tatactgatg accagttaag tgatttgtcc aataatcctg agattaaagc 31260 aagtattgaa caagcaaatc aagaagcgca agaagcttta aaatcataca ttgatgctca 31320 agatgatctt aaagagaagg aatcgcaagc gtatgctgat ggtaaaattt cggaagaaga 31380 gcaacgcgct atacaagatg ctcaagctaa acttgaagag gcaaaacaaa acgcagaact 31440 aaaggctaga aacgctgaaa agaaagctaa tgcttataca gacaacaagg tcaaagaaag 31500 cacagatgca cagaggaaaa cattgactcg ctatggttct caaattatac aaaatggtaa 31560 ggaaatcaaa ttaagaacta caaaagaaga gtttaatgct tctaaaagaa cactatcaag 31620 agtgttagca gacatcactg taaatgctat gaaaggcatc tatttaaggt atgacgaaaa 31680 tggggcgatt acttcacata ctattgataa agatggcgtg aaaattagtg gcgataaagt 31740 tgatataaca gcgaatagag aatttaatgt agtcgcaaat aatattaata acaaagttgg 31800 taaaaatgac attgttaata gcctaaactt atcaaatgaa ggtcttgaca tcaatgtgaa 31860 tagaattggt attaaaggcg gaaatgctaa ccgttatgta caagttcaaa atgattttat 31920 tgaacttggc ggaatcgtac aacgaacttg gaaaggcaaa cgatcaaccg atgatatatt 31980 cacacgtctt aaagatggac atctaaggtt tagaaataat accgcaggcg gttcacttta 32040 tatgtcacat tttggtattt caacatatat tgatggagaa ggcgaagacg gaggttcatc 32100 cggtactatt caatggtggg ataaaactta cagtgatagc ggtatgaatg gcataacaat 32160 caattcttat ggcggtgtag tcgctttaac atctgactac aaccgaatta ttatcgattc 32220 atatgcttca gctaatattg aaagtagaga agcaccgata tatttatctc cgaacaccaa 32280 aaataaacct ggtttaaacc gattcgcatt cacattatca aacgctgata gtgcatacga 32340 aactgacggt tatatcatgt ttggttcaga tgaaaactat aagtacggtg ctggattaag 32400 attttctaaa cgtagcaata aaggattggt tcaagtcgtt aatggtgact atgctacagg 32460 cggagacact acaattgagt caggtatggg caaattcaac ttagttaaac gaagagatgg 32520 aaatagttac gttagcattc aaagttatga tttattggcg gtaggttctg ataatgctgg 32580 cgatagagtc gcttctaatt ctatttataa gcgtacttat tcagcacctg ctaacttaca 32640 cattacttct gctggaacaa ttgggcgtgc tacttctgcc aaaaagtata aaatttcaat 32700 cgaaaatcaa tatatcaatg aagacgatca gttcagtcat tcaaaagaga ttttaaagct 32760 tccaattcgt acatggtttg acaaatatga atcggaaata atggctaaag aattggaaag 32820 tggtaaaaag ttatctgatg atacttttaa acttagtcga catactggct taatagcgga 32880 agaggttgaa gaattaggat ttaatgaatt tgttatttat gatgacaacg gagaaatcga 32940 aggtatcgca tacgatagac tttgggttca tttaatacct attattaaaa accagcaatc 33000 aaaaatcgaa aaactggagg aattaataaa tgaatgatag caatcaaggt ttacaagcca 33060 atccacaata tacaattcac tatttatcgc aagaaatcac aagactaaca caagaaaatg 33120 caatgttaaa agcatatata caagaacaaa atgaaaaaag caaaagtgct gaggaagagt 33180 aatccttggc actattttta tacaaaaatt taaggaggtc atttaatatg gcaaatgaaa 33240 ttatcaaaaa aacagagaga tttattttag tacaaattga caaagaggga acagagcgcg 33300 ttttgtatca agattttgta ggcagtttta caacgtccga ttcagcaagt tatgcacaag 33360 attttaaatc tgaggaaaac gctaaaaaga ttgctgaaac tttaaatctt ttatatcaat 33420 taacaggcaa tcaaaacggt gtgaaagttg tgaaagaagt tgtggataga actgacttgt 33480 catctgataa atcagttgat agcgaaataa tgtaactata ctaagttatg agcattacgc 33540 tcatagcttt cttagaaagt aggtgtagtt ttggatgata ttcagaaaat aaaaaaagag 33600 ctttctgaat tagttgaacg tgttgatgat gttgaaatac tagcaaacga aacagctgat 33660 catgtgcttg aacttagaga ggaacataag caacatcata atgaactaag agaatctcat 33720 aaagaactta aagataagca agataaagtt gtagatgaga atttagagca aacaaagata 33780 ttaaacagaa ttgaagaaag atatcaaacg caagtagatg ttgcgcaaaa aaatgaagaa 33840 aagacactcg cccaaaataa atggctcgta ggtgccatat gggcgcttgt aacaattgtt 33900 atgattgcag tcattactgc atcaattact gcgttattac cttaagggag gtggacataa 33960 tgagttgggc aagatggttg tcatgttatt tgtatggtcg taaatgtaaa taatgttttt 34020 ggtcagtgca tcggcactgg ctttttattt attgttgtaa ttatggtaat atgcagaagt 34080 gagcaagttg gatagatggt ggctatctga gtataaggag gtggtgccta tgttggcatt 34140 actgaaatct ttagaaagga gatgcctaat gattacaatt agtaccatgt tgcagtttgg 34200 tttattcctt attgcattga taggtctagt aatcaagctt attgaattaa gcaataaaaa 34260 ataaccatcg ctaactttgg ctggtttcga tggttaaatg gttattaatt taatctttaa 34320 tctaaaatag ccaccgtctt tttaacgggc tcattagggt aacatgtttg cgcatgttgc 34380 cctttttcta tatataaatt aacacaccat aatataaata tcaaatagac ggcttattag 34440 tcgtcttttt attttgggta aaaggagata agaatatgat taattggaaa attagaatga 34500 aacaaaaatc attttgggta gcgatattgt cagctatctt tttatttgct caaaacatcg 34560 caaaagctat tgggtatgat atccaagttt atacagagca attaacagac ggtttaaacg 34620 ctatattagg atttttagta ttaactggtg tgattcaaga cccgactact aaaggtatag 34680 gtgatagcca ccaagcttta gaatatgaag aaccaagaag aaaatactag 34730 <110> Optipharm.CO., LTD <120> Novel Staphylococcus specific bacteriophage SA7 and antibacterial          composition comprising the same <130> 1-20P <160> 1 <170> KoPatentin 3.0 <210> 1 <211> 34730 <212> DNA <213> Unknown <220> <223> Bacteriophage SA7 <400> 1 atgcaagcat tacaaacatt taattttaaa gagctaccag taagaacagt agaaattgaa 60 aacgaacctt attttgtagg aaaagatatt gctgagattt taggatatgc aagagcagac 120 aatgccatta gaaatcatgt tgatagcgag gacaagctga cgcaccaatt tagtgcatca 180 ggtcaaaaca gaaatatgat cattatcaac gaatcaggat tatacagtct aatcttcgat 240 gcttctaaac aaagcaaaaa cgaaaaaatt agagaaaccg ctagaaaatt caaacgctgg 300 gtaacatcag atgtcctacc agctattcgc aaacacggta tctacgcaac agacaatgta 360 attgaacaaa cattaaaaga tccagactac atcattacag tgttgactga gtataagaaa 420 gaaaaagagc aaaacttact tttacaacaa gaaatcggag agctaaaacc caaagcagat 480 tatgttgatg aaatcttaaa atcaactggc acattagcta caactcaaat cgcggcagac 540 tacggtatat cagcacaaaa gttaaacaaa ctactacacg aagctagatt acaacgaaaa 600 gtaaataaac agtgggtgct ttactcagaa cacatgggca agagttacac agaatcagac 660 actatagcaa ttgtacgctc tgacggtaga gaagacacag ttttacaaac tagatggaca 720 caaaaaggca gattgaaaat acatgaaatc atgactgaat tcggttatga agctaacgta 780 actgcttaac aggaggaacg aacaatgcaa gctcaaaaca aaaaagtcat ctattactac 840 tatgacgaag aaggtaatag acgactatta tcaattggga atttggaaca ttatttatta 900 gcagatatca aatcaaggtt tgatttatat aaaaagaaaa tacctgactt agataatctg 960 ttcgttcaaa tagacggtgt tgaatttaaa ttactatagc ccgagcatct tgttaacgac 1020 tgacgatgcg atttgttgaa ttatagggat tgaaaccgaa gaaacttttg acgctttagc 1080 tttagtttct ctccaaactt cgacatctct aacatcatcc aaaaggttgt gacctgaaaa 1140 attcatatgt ttaacaaaat aaccttccat atagaattca gcgtctatat aacctgcacc 1200 ggtcaattgt ttaacagtgt attcgatgtc ttcacgtgag aaatttttaa ttgtattttc 1260 taggtcttca ttatctagaa cattatttaa ttttaaatca ctctctataa ctaaaagaac 1320 ttcacgtatg caatcgtgtt ttaacttcat acgaattcac ctccttaata ggagtatagc 1380 agaaaggagc ataaacaata tggaagatat gaaagaactt tattctttaa aaatccaaaa 1440 gaagaattta aataataaac aaaagaattt aatgtctgta attaatcaat gtattgaact 1500 agaaaaattt tcttacactg aaattaaaaa agttctctac ctaattgata gagaacaaaa 1560 gtatttagct aataaccgca gaaaaacata agttaaaaat aatctaactc ggactgctgg 1620 caatcttcta aatatttttc atactgattt ttagttccgc ccagaacgta ttcagtattg 1680 tagtacgctt gtccattatc caaaatttta actaattttg taccaacatg aacgatatcc 1740 caaccttctt ttaacagatc gttggctgca tcattagcta aatcgtcatc gaaagacaaa 1800 aggtgatagt agtttttcat aatattcacc tcctctctgt aggagataac aacattatac 1860 acgaaaggaa tgatagaaat gccacatgta ttaaacgtaa ccgttccaat acctgaaaca 1920 catgtactta tcacaaaaga tgaatatgat gagctaattg gttatacatt agaccctgta 1980 tggaacatga gtgacttaaa gaagaaatta aaaattgcat ctgatgagac tatcaaggac 2040 agattactat ttcatcctag atttgaaaaa gaactaagag cgcaaggaat tgtgcattac 2100 ccagatgaga attttaatcg ctggagattt aacgcaagaa agatgaataa attcgtcgat 2160 gagcatttca atgaaatata taaggagaga ataaaatgag caacatttat aaaagctacc 2220 tagtagcagt actgtgcttt acagtcttag caattgtact tatgccgttt ctatacttca 2280 ctactgcatg gtcgattgcg ggattcgcaa gtatcgcaac attcatattt tataaggaat 2340 acttttatga agaataaaaa aactgttact cacggcaatg agtaacagtc taaacaatta 2400 gaaaattaat gcatattcaa tataaaacga aataaaggaa gtgtcaacaa tgtactacaa 2460 aattggcgat gtatgtcaaa aagtaattaa tgtagacgga ttcgatttta aattagcagt 2520 taagaaacaa gattacagca ttctagtgaa tgtcttagat ttagaagata gatttatcga 2580 cggtataaat ataacagatg agaatgatct atacacagca ttagacatat taaatcaatc 2640 tatttatgaa tggattgaag agaacacaga cgaaagagac aggctaatta acttagtcat 2700 gagatggtag gtataagcat gagagataca gaaagaaata tattgaatat ttttaagacg 2760 ttattcgacg aatatacttt gtcaaaccaa cgagcattat tggaaattga acgtaatcat 2820 cacggatact tatcgattaa tttcttgcac tatcacgaca gttacaaaac gaacaataag 2880 cttgtacaga tacatgaaat caatccggac agccacgaac gaataaaaaa tttaattatc 2940 gaggtgttaa gaggtcaccg aaagattaaa aaaggagcat gatgatggat ataaaaataa 3000 ataagctaac aatatcaaac tttgctggaa tcaaagaaga aagctttaac tttgacggta 3060 aagacacaaa aatatacggc aataatgcga ctggtaagac tacgactgca accgcattac 3120 aatggctgct tttcgataaa ggtttggacg gatcaaccaa atcatttaac cctgtacctt 3180 taaacgaaaa aaacgaagaa aattatgagt taattccgac tgttttcgca gaatttgaaa 3240 tcgacggaaa aataacgact ttcaaaaaag agtcacatcc taaatacaca ataaatcaaa 3300 agacgaatcg caaggaatac tcacgaagta gaacaaagaa acaatatatc aatgatgaat 3360 caataaaagt aaaggattat aaagctcgta ttgatgaact aattgatgaa gatgtattca 3420 agttgattac aaatccccaa gcatttaatt tactcgattg gaagaaacga agaagtttgt 3480 tatttgaaat tgcaaaacca attaatgatg aggatgtcat taaaacaaat aacgacttta 3540 aaaaattaaa taatattctt ggtgatcatg aaattgaaac aaagaaaaag attcttactg 3600 acaagataaa gcagattaac aaagacatca aagatattcc gatacgtatt aatcaaacac 3660 aacaaaataa gcaggatgta ccagaattcg ataacgatag atacgcaatt atcaaacaag 3720 aaattgagca acttgaaaat gagcgtatag atattcaaaa cggtaaggaa gaaattaatt 3780 tgcgtaatca attagctgat aaacaatcag aattgaaacg catagaagac aataacagcg 3840 caagtaatga gaacaaaatt tatgctttaa caaatgagtt acacgttgaa aatggaacgg 3900 ttgcgaacct taaaacgaga ttaaagcaaa acaaacaaca aattacgcat gaagaaaata 3960 gacgtaatca attattggaa aatcacaaag gactaaaaag tgatttagaa aaatctaaaa 4020 atcaaaaatt tgaacatctt gatgacaatg tatgtagctg ttgcggtcaa cagttaccaa 4080 ctgaacaagt gaatgaggca agagaaaaag ctttacagaa attcaatgta aaaaaatcga 4140 aagaattaga aacaatacaa acatctatca atcacattat ttcagaagga aagaaaataa 4200 agccaatcat cgagaagtta gaggatgaca acaataatct acaaattaaa atcaacgaag 4260 cagaagagcg ttcagcaaga atacaaaaca aaattaataa gttgaaaacg actcatgttg 4320 acgttacaca aactgacgaa tacaaagcag taatgttaga gataaacgag attaatcaaa 4380 aacgctcgaa cattaggaaa actattcaag ataacgtttc aggaatagat gacaaaataa 4440 gcgaacttac tcaagaaaaa tcagaaattg aagtgtcaag atcaatcgaa aaatcaaata 4500 aacatctaga tgatgttatt tctgaattaa gaaatgaaga agatagatta ttggatgaaa 4560 aagaaaagta ttcacatgac ctttatatct taaaagaatt tacaacaaca aaagtcaaaa 4620 tgcttactga aaatatcaat aatgaatttg agattgctga atttaagtta ttcaatacct 4680 tagttaacgg cgaattagaa gaaacatgtt ccacaacggt taacggcgtc gaatacgaca 4740 gcggtttaaa taacgcctca agaattaatg ttggcttaga tatcatcaat acactgtcaa 4800 aacattttaa agttacagcg ccaatattta ttgataatgc tgaatcagta acagagctta 4860 tcaaaacaga atcacaacaa attcaattga tagtaaatga acaagataaa aaaataagaa 4920 tggagactat ataaaatgac tgaaaataat aaattacaaa ctattgaaca acaattagta 4980 caagaaaaga acgtatctga caacgtatta aacaaagtga gagttttaga gtcacaaggc 5040 aatttggaat tgccaaatga ttattcacca agtaatgcca tgaaacaagc atggttacaa 5100 atcagccaag ataacaaatt aatgagttgt aacgatacaa gcaaagcaaa tgccttatta 5160 gacatggtaa cgcaaggttt aaatccagct aaaaatcaat gctactttat tccttacggc 5220 aacaaaatgc agttacaacg tagctatcac ggtaatgtaa tgatgttaaa acgtgatgca 5280 ggtgctcaag atgttgttgc tcaagtgatt tataaaggcg atacattcaa gcaagaaatg 5340 ggaggaacag gacgtatcaa agcgattaaa cacgaacaag acttctttaa catcgacaaa 5400 gaaaacatta tcggtgcgta ctgcacaatc gtatttaatg atggacgaga taactatatt 5460 gaagtcatga ctattgaaca aattaaacaa gcatggatgc agtcatcaat gattaaagat 5520 gaaaaagcat tacaaaattc taaaacacat aataatttca aagaagaaat ggctaaaaaa 5580 acagttatca atagagctgc taaacgttat atcaacacat caacagatag caatcttttc 5640 aaatacgcac aagaatccga acaacgtcaa cgcaaagaag tgttggacgc agaagttgaa 5700 gaaaatgcaa atcaagaaca attggacttt gaacaaccag ttctcgaaga agcacaatac 5760 acagaattag aaaatgataa gcctattgat gtatctgact ttgaagaaat aaaagaacct 5820 gcaacagaaa aagaaagcga agaagagcca ttttaattga aacaatagca actggttcaa 5880 gtggtaactg ctacgtctta aatgatggac gtactacgtt actacttgag tcaggtataa 5940 aatttgaacg tgttcaaaag cattttaaat ataaaacaag acatatagca gggtgtctta 6000 tcacacacga acatggtgat catgcaaagt acacaaagca gtttgtcgac aatggtgtaa 6060 tcagctatat gactgctgga acacaacaag ctatgaattt tgaaagtcat cgcttatgca 6120 cgattaaggc aaagcaagag ctgcgaatag gcacatggtc aattctaccg tttgacatcg 6180 aacatgatgc taacgagcct gtggctttct tattacaaag tacattaggt tataaggttc 6240 tgtatgttac tgatacaaag tatttgaaat acaaatttaa cggcattacg cacatgatgt 6300 tagaagttaa ttatatctat gaacaaatgc aggaaaacat aaaaaacggc agtgtgcaca 6360 gcacattagc aaacagaatt atggagtctc attttagctt agaacatgct atcggaatgt 6420 taaaagcaaa tgatttaact agactcgaag aaatacattt aattcattta agtagtcaaa 6480 attcaaatgc aaaatacatt aaaagtgaaa tacaaaaagt gacgggcgcg cccgtttatg 6540 ttggaggttt ataaatgcta aacagaacaa tattagttgg tcgtttaact agagacccag 6600 aattaagaac cactcaaagt ggtgtaaatg tagcatcatt cacattagca gttaaccgca 6660 catttacgaa tgcacaagga gagcgcgagg cagactttat taatatcatc gtatttaaaa 6720 aacaagcaga gaacgttaat aaatacctat ctaaaggatc gttgacgggc gtagatggta 6780 ggttacaaac gcggaattat gaaaataagg aaggtcaacg tgtatatgtt acggaagtta 6840 ttgctgatag tattcaattt ttagaaccga aaaactcaaa tgacactcaa caagatttat 6900 accaacaaca agtacaacaa acacgtggac aatcgcaata ttcaaataac aaaccagtaa 6960 aagataatcc gtttgcgaat gcaaatggtc cgattgaaat agatgacaat gatttaccat 7020 tctaatttaa ccggtttgaa agtgaggtgt gtatatgact ggttggataa gtattgatcg 7080 ctcaattcaa aatcattggc tatttaaaga aaagagaaca ttttcaaagt ttgaagcatg 7140 gatatattta ctcatggaag cgaatcattc aaaggcaaaa gtgcctattg gaaaccaaat 7200 tgtaaccgta gaaagaggac aaagattaac atcgattttg accttgtctg acctttttaa 7260 ctggtcacga tttaaagtga aaaccttcct tgacttactc gagagtgatg gaatgttaga 7320 agtcaaaaca acatcaaaat atacccttat aaccattgtc aattatgact tttatcaaag 7380 tgagcaggga aggaaccaac atcaaaacga catcaaacca acatcaaaac aacatcagtc 7440 aaacatcaat ccaacatcaa aacaacatca aaccaacaca aacaataatg ataataaaga 7500 taataatgaa aagaatgtga ataatgagaa gaagaaggca gctgccttcg acttcttcca 7560 agataacgga ttcggtttca taactcctta caatttagac gatttaaatt actatcttga 7620 ttcatttgaa aatgattcag atcaaatagt taccgcatca cttaaaatcg ctaaagacag 7680 aaataaagtt acttggggat atgctaaaag cattttgaat acatggctta atgcaaactt 7740 gaaatctatt gaacaagtac gtgcatttga aaagcaacaa ctggaaagca aaaagcaaac 7800 taataaacct tatgttaaac catcgaaaga aaaaacaccc aaatggctta cagacagcac 7860 gagagaaacg aaaacgccgg aagtagatga aaaccttgag aaagacagag aagcttttat 7920 taagcgtcta aatagcaaat gggagtgatt gaaaatggat gcatttgata aatactatct 7980 atttgatcat gacggcaaca aaatgttttc agttacacca cattttaaag atggtcggca 8040 tttagttgtt ggaataaaag aaacaaaatt taatggtcgt cgttggtatt tagacgatta 8100 tgaattaaat acacttattg ataatgaaca aatggagtta ggacaccaaa caagcttatt 8160 tgaatatata tgagggatta catggagata gaaattaaat ttaatgaagt gtttaatgcg 8220 ccgatggggt cgccccgtcc acgctttcgt aaaacaggta gatttgttca aacttacatg 8280 ccaacgtctt acacaaagca taaagcgtat atacaagggc aaatgcctaa gttaaatcta 8340 gagcgcgcac taaaaatcga attagacttt tactttccat tgcttaaatc gtggtcgaag 8400 aaaaagaaaa gcgaaatggt tgggcagtat aaagtgacta agccggatat cgacaactta 8460 attaaaacgg tattagatgc ttgtaatggc catgtatgga aagacgataa ccaaattaca 8520 gaaataacta gctcaaagcg ttatggaatt gagcccaaaa taatcatacg aatagaagaa 8580 atataagagg tggataaaat ggcgagaaaa gcaagaattg taacaataaa cgataaacct 8640 tataggttca gtaaatttga aatggaatta atagaaagtc acggtataac cgctggaatg 8700 gtttctaaga gagtaaaaga cggttgggaa ctacatgaag caatggacgc accagaaggt 8760 acgcgtttaa gcgagtacag agaaaagaaa acaatagaaa gactggaaca agctagactc 8820 gaacgcaaat tggaaagaaa gcaaaagaaa gaggctgagc taagaagaaa gaagccacat 8880 ttgtttaatg taccacagaa acatccaaga ggacgttatg cgtgctacct gatggaaaac 8940 gacatattcg tgaaagttaa gaagtagatc atgacagata acgcacgcaa agaataccta 9000 aatcaattct ttggatctaa gagatatctg tatcaggata acgaacgagt ggcacatatt 9060 catgtagtaa acggcactta ttactttcat gggcatatcg taccaggttg gcaaggcgtt 9120 aaaaagatgt ttgatacagc agaagagctc gaaacatata taaagcaaca tggtttggaa 9180 tacgaggaac agaagcaact aactttattt tagaggagat ataaaaatga aaatcaaatt 9240 taaaaaagaa atgacattag atgaattaat taagtgggca tgggagaacc ctgaattagt 9300 aagaggagag aaattttatg cgcaaggcaa gagtaatgaa acatatgtgt atttccatct 9360 ttacgacgga agaaagtgca tcttaagaga atatatatca gccgatgaca cttttgaagt 9420 cgaatatgaa gaggaaatca cggaagaaac tgtaataccg aagttagtaa aaatgtacaa 9480 agacggaaaa atgtccgttt acaatgacta ttcgattaag cgttctttgc tttattcccc 9540 taaagcatac tatatcttaa acgacgacct aactatgacg ttaatctgga aagatgggga 9600 gttggtagaa tgatgcaaac ctataaagta agtctttgta tcaagttctt agcgtctaaa 9660 tgtaattata aattaaaaaa gcattatttt gtgcaaagta cgaatgagga agaagccacg 9720 aatacggtat taaaactgac tcgtaaaaag ctcccgttcc aaactgcaag catagaggtc 9780 gaaaaagtgg aggtagtagt atgatgccga aatatcgagt gtgggacgaa tatacaggaa 9840 gaatacacga tgttgtagga ttcgacttca ttgagactga agttcactat gaaaactacg 9900 cggaagcaga agctttaata catgcaagag attttaaaga tgtagaactt atgcaaagta 9960 caggacttaa agacaaaaac aacaacgaaa tatatgcggg agatatagtt gagtttgaag 10020 atgaaatatt agagatgcca gacgatgaat ctgtaatagg aacaattaat agagcagtaa 10080 tatctattga tgttgtaaat ggtattcaat taaaagattt tatgtttgag ggcgcagtct 10140 ccgaaaatga ttactttgag tatatagaca taaaatcctt ccttagatat gactgtgagg 10200 ttaaaggcaa catatttgaa tcatcacatt tattggaggt aacagaatga actatgaaac 10260 aggggtccaa ctaggtgtaa tggacgctag gttgaagaag atgagaaaac aacgtgatga 10320 gtacaagaag caacgtgatg agcttattgg ggatataggt aagttaagag aacgcaacaa 10380 agagctggag aagaaagcaa gtgcatggga taggtattgc aagagcgttg aaaaagattt 10440 aataaacgaa tttggcaaag atggtgaaag agttaaattt ggaatggaat taaacaataa 10500 aacttttatg gaggaagaca ctaatgaata accgtgaaca aatagaacaa tccgttataa 10560 gtgctagtgc gtataacggc aatgacacag agggattact aaaagagatt gaggacgtat 10620 ataagaaagc gcaagcgttt gatgaaatac ttgagggaat gacaaatgct attcaacatt 10680 cagttaaaga aggtattgaa cttgatgaag cagtagggat tatgacgggt caagttgtct 10740 ataaatatga ggaggcacag gaaaatgact aacacattaa caattgatca gttacaagag 10800 ttattacaaa tacaaaagga gttcgacgat agaataccaa cgctgaactt acgagatagc 10860 aaaatagcat atgtagttga attctttgaa tggtttaata cattggaaac gtttaagaac 10920 tggaagaaga aaccaggtaa gccgttagac gtacaacttg atgaattagc tgacatgttg 10980 gcgtttggat tgagtattgc gaatcaagta ggagtgtcat cagaagagat aaaagaagcg 11040 attgaatcaa gttttaaaga tacagaattt cacaaaatgt ttaattttaa agataaagaa 11100 tttgctcaag acgcagttgt tagtacacca cagataatat tcaaagaatt ttatcccgac 11160 caacaagcaa ttgttatagt gatagacata gcttacaact tatattctat cgaccaactc 11220 attgacgcat acaaaaagaa aatgaaaagg aatcatgaaa gacaagatgg aacagcagac 11280 gcaggaaaag gatacgtgta aagacatatt agatcgagtc aaggaggttt tggggaagtg 11340 acacaatacc tagtcacaac attcaaagat tcaacaggac gcaagcatac acacataact 11400 aaagctaaga gcaatcaaag gtttacagtt gttgaggcag agagtaaaga agaagcgaaa 11460 gagaggtacg aggcgcaagt taaaagaggt gcagttatta aagtgggtca gttgtttgaa 11520 aatataaggg agtgtgggaa atgattaagc aaatactaag attattattc ctactagcaa 11580 tgtacgagtt aggtaagtat gtaactgagc aagtatatat tatgatgacg gctaatgatg 11640 atgtagaggc gtcgagtgat tacgtctttc gagcggaggt gagtgaataa tgagaatatt 11700 tatttatgat ttgatcgttt tgctgtttgc tttcttaata tccatatata ttattgatga 11760 tggagtgata ataaatgcat taggaatttt tggtatgtat aaaattatag attccttttc 11820 agaaaatatt ataaagaggt agataaaaat gaacgagcaa ataataggaa gcatatatac 11880 tttagcagga ggtgttgtgc tttattcagt taaagagatt tttaggtatt ttacagattc 11940 taacttacaa cgtaaaaaaa tcaatttaga acaaatatat ccgatatatt tagattgttt 12000 taaaaaggct aaaaagatga ttggagctta tattattcca acagaacagc atgaattttt 12060 agattttttt gatattgaag tctttaataa tttagataag caaagtaaaa aagcgtatga 12120 aaatgttatt ggatttagac aaatgattaa tttatcaaat agagttaagg caatggaaga 12180 ttttaagatg agtttcaaca atgaatttag tacaaatcag atttttttta atccttcttt 12240 tgttatggaa acaattgcta ttataaatga atatcaaaaa gatatatctt atttaaaaaa 12300 tataattaat aaaatgaatg aaaatagagc ttataatcat attgatagtt ttatcacttc 12360 agagtaccga cgaaaaataa acgattataa tctttatctt gataaatttg aagaacagtt 12420 tagtcaaaag tttaaaataa acagaacttc gataaaagaa agaattatta ttaatttaaa 12480 caagaggaga tttaaatgat gtggattact atgactattg tatttgctat attgctatta 12540 gtttgtatca gtattaatag tgatcgtgca agagagatac aagcactcag atatatgaat 12600 gattatctac ttgatgaagt agttaaaact aaaggataca acgggttaga agaatacagg 12660 attgaattga agcgaatgaa taacgatatt aaaaagtaat ttatattatc ggaggtattg 12720 catgtataac aggaaagaaa tacgtgaaat gatagataac tacaagtgga tgaagaacat 12780 aatagacagt aaagtctacg ataacgaaag tacatcaatt gcacaatatg gttatcaatc 12840 tgcgatgcca aaagctaaag gcacgactag caataaagtg ttagtgaaag ttataaacaa 12900 aaacaaagcg cttagaaagt acgattactt gattaagaag atagcgttca ttgatgaata 12960 tgaagaatac atcacgaatg aaaaagatta tcatatttta caaatgttaa aacaacgaga 13020 aagccataat aggattatga gtattcttga tataggcaga gacaattttt attctagagt 13080 aaaagatata gtaaatatac tttataactt gcaacaagaa accgacacat cgtacacatc 13140 ggacagttcg gacacatcgt acaaatcgta cacatcggac taattttgat gctacatatt 13200 gttttttatt ataattgcta tgtagcaaaa catttatatt tattttgaac tctcacatta 13260 agtgagggtt tttattttta taaacaagag gtggagaatg gagatatcaa agtaccaaga 13320 gatagctaca cgtacacaca atgatgaatt gaatttaaat gaatctatta cttgttacgg 13380 cttaggttta actcaatcta cagacaatgt tacagatcta attaaacagc atatgttttg 13440 taatgtaccg atagataaag gaattatgat aaatgaactt agcgaagcat tgtggaatat 13500 agctaatctt actaacgtgt taggtattaa cttggatgag atagctggtc atagtgttaa 13560 cactatcttg atgaataaac ctaatcagac tatcaattta gacaatggta taaaacaagg 13620 agacaaagta ttgtttcaag gtagtaagta tcttgttgat ggatcgatag gaaacttatt 13680 gttaattagc aatgataaag atgatagaca agtaactgtg caagatgtta agaaagtcga 13740 caaggagtga tgtgcattgt ctattatgaa gcgatgtggt catccaacat gtaatgtatt 13800 gattaatcat aatgaaagtt attgtgataa acacaagcaa tatgcaaatg aaaattacaa 13860 tgatttgaga cgtcgaaacg atccagagta tttaagattt tataaatcga aaacgtggca 13920 aaacatgcgt cgaattgtat tgttagaaca tgattttatt tgtgtttctt gtggcaatca 13980 agcgactatg gttgaccata ttgtaccaac aaaaattgat tgggcaagaa gattagacaa 14040 aagtaattta cagcctttgt gtgatgcttg ccataaccaa aagacaaaag aagatttgaa 14100 gaaatattaa aaaagataaa aataggaagt ccccccaaag atgaaacggg cgtcaatgaa 14160 aggttctgga gaacggagca gagttttctt ctcaaaaaat tccctttatt taagtttttt 14220 tagtaggagg tgctaattta tggcgggtag acctaagaag cttttgtcaa attcgaacaa 14280 gaattataca aaagaagaaa ttattgaaaa agagcgtcaa gaagctcaat taaataaatt 14340 ttctaaaatc gatactgaac caccgcactt tttagatgaa atagcgaaac aagaatactt 14400 aagaatatta ccgcacatgc aagaattgcc aatttccaac ttagataaag cacaattagc 14460 acaatattgt agtttttata gtgactttgt taaagcaagt ttgattttag agcgcgaaga 14520 cttgatttta gaagacgaca aaggaaatca aaaggttaat ccggcgttca acataaagga 14580 aaaagcgggt attcgattgc aacaaacagc taatacttta ggattaacta ttgatagccg 14640 attgcgtatt atggttcctg atgaaaaaga agatgatgat ccatatatgg aatttgtgag 14700 tgattagtaa tgactgatta tgttactaaa tacgcaaaaa aggtagtttc aggagaaatt 14760 ttggcaagtt tgaagaatat tcaagtatgt aaacgtcacc tatcttttat ggagaacccg 14820 ccgaatggtt gccattggga taatcatttg tctaacaaag caattaaatt tgtggaaatg 14880 cttccagacc ctaaaacaaa ccagcccatg cctcttatgg agtttcagaa attcattgtt 14940 gggagcttat acggctggcg tagaggtcaa tacagaatgt ttactaaagc ttatataagt 15000 atggctagaa aacaaggtaa gtctctaatc gtatcgggaa tgtccgttaa cgaactgttg 15060 tttggacaat accctaaatt taatagacaa atttatgtag cttcatctac ttataagcaa 15120 gcgcaaacaa tattcaagat ggcaagccaa caagtaaacc taatgcgaag taaaagcaag 15180 tttatccgtg aaaaaacaga cgtaagaaag acagacattg aagatgtatt aagtagttca 15240 gtgtttgcac ctctttccaa taacccagat gcggttgatg gtaaagatcc tacagttgtt 15300 attttggacg aattggcaag tatgcctgat gatgagatgt actcaaggtt taaaacaggt 15360 atgacattac aaaaaaatcc tttaacccta cttgtttcaa cggccggaga caatttaaat 15420 agtcaaatgt accaagagta taagtatatt aaacgtattt taaatgaaga agtaagagct 15480 gataattact ttgtatattg tgctgaaatg gattcacaag aagaagttca agatgaaaca 15540 aagtggatta aagcaatgcc gcttttagaa tcaaaagaac atagaaaaac tatacttcaa 15600 aatgtaaaag ctgatataca agacgaatta gaaaaaggga catcatatca taagattttg 15660 attaaaaact tcaatttatg gcaagcgcaa agagaagata gcttgctaga tatttcagat 15720 tgggaacaag taataacgcc tatgcctaat atcaatggta aagatgtgta tataggtgtc 15780 gt; aaagtgtttt tacatagtca ttctttcatt ggattaagaa caaacttaga acaaaaatct 15900 aagagagaca aaataaatta tgaattagcg attgaacgtg gcgaagctga gactacacaa 15960 tcagatagcg gcatgattga ttataaacaa gttatcgatt ttatagtgaa atttataacg 16020 acgcatgacc tgaatgtaca ggctgtttgc tatgaccctt ggaatgcgca aagttttata 16080 acaacaatcg aatcaatggc tttagattgg ccactcattg aagtgggaca aagttttaag 16140 gcgttatcac aatctattaa agaatttaga atgtgggttg cagatgaaag aatacagcat 16200 aacgataata tgttacttac aacatcagtt aataatgccg ttttgattcg tgacggagaa 16260 gacaatgtga aaataaataa aaaaatgaat cgtcaaaaaa tagatccgat tatttcgatt 16320 atcacagctt tcactgaagc tagaatgcac gaattccaag aaaattggac ggagaaatat 16380 gaaagcgaag aattcggatt ttaaaggtgg tgacaaaatg gacttgaata aaataaatgt 16440 cttttttaat ttcttggttg ctaatttggt tagcatcctt tttttattag gtttgtttgt 16500 ggttaatgtt tctgtgtata aagcattcgg tcaaaatata ggacttttat gcattggtat 16560 aacactgatt gttgtttcgt tgattttaaa tcatgaaagc aatcaagaaa ggagttagta 16620 gttgtgggga ttttttataa aaatgaaaaa cgagacttgc aatacaacga agatgatttg 16680 caaatgatgg ttcaaacttt gccaggtttt caaggaacaa aattacgaca atataaagat 16740 atagaagcaa ttaggcatag cgacatcttt actgcagtta tgatgattgc ttctgatttg 16800 gcgcgcatgc caattagggt gacagtgaac ggccaaatta attatagtga caggattgtt 16860 aatttgttaa atacacgtcc taacccaatg tataacggct atatattcaa attagtagtg 16920 tttgttagtg ccttactaac atcgcacggc tatattgaaa ttacacgtga taaaacagga 16980 gaacctatga atttaacgtt cagaaagaca tccgaaatag aattgaaatc agacgcaaga 17040 ggtcgactgt attattttca tcaaaggata gacagtaacg gaaataatat agaacgtaat 17100 gttaagtttg aggatatgct agacatcaaa ttttattcgt tggatggtat aaatggtttg 17160 tcactgttag acacattaag tcgcacgata gaatcagata acaatggaaa agatttcctt 17220 aataatttct tgcgaaatgg cacacatgct ggtggtattt tgaaaatgaa aggtgtatta 17280 gataataaaa aagcaagaga ccgtgccaga gaagaatttc acaaaagttt tagtggaact 17340 aaacaagctg ggaaagttgt cgtactcgat gaatcaatga cgtttgatca attagaagtt 17400 gatacagaag ttttaaagct tatcagagaa aacaaatcat caacaagaga aatagcaggt 17460 gtatttggta ttccattgca taagttcggc atagaaacag cgaacatgag tatcacggat 17520 gctaatttag attacttatc aactttaaaa ccttatatta catgcgtttg tgcagaattg 17580 aattttaagt ttaatgatga atatgtgaat cgtgaattta aatttgatac cactgaaata 17640 cgagttgttg atgaaaaaac acaagctgaa attgacaaaa ttaacattga ttctggaaag 17700 atgaatatcg atgaaattag acaacgtgat ggattagcgc caatatcagg cggtaatggt 17760 agcattcaca gagtcgattt aaaccatgta aatattgaac ttgtagatga gtatcagatg 17820 aataaatcga gagctactga taaaaaattg aaaggtggtg aggaaaatga gtaaggaaac 17880 gagagttggc aacattattg aggtacgctc aaatgataac aacgaaatgg tcatagaggg 17940 gtatgcgtta aagtttgaca cttggtctga aaatcttggt ggattcaaag aaacgatttc 18000 acgtcgcgct ttagaaaaca ctgatttatc tgatgtgcgt tgtttagtag atcatatccc 18060 atcgcaaata attggtagga caaaatcggg tactttggag ctcgaaactg atgatgttgg 18120 acttaaatat cgttgtaagt taccaaacac aacatttgca cgtgatttat atgagaacat 18180 gcgtgtaggc aacatcaatc aatgttcgtt tggttttatg cttgacgata aaggcgatga 18240 agtgcgtttt gatgaacaag aaaacattta caaacgtact ttaacagcaa ttcgtgaact 18300 tacagatgtt tctgtagtga cttatccggc ttacaaagac actgatgtta aaccagcatt 18360 acgtagtatt gaaaccgtta aaaaagaaca acgtaaaaaa gaattagaaa taagactaaa 18420 gaaacactct atattaaata atatttggtg aagttgaaca ccattatcaa atacagccat 18480 tggacatgct gaatatagcg atgtctattt ttttatgcca attttaggag gaaattaaat 18540 gaaaacaaaa gaagagttac aatctgagat ttcagacatt aaaagacaaa ttgatttaaa 18600 ggtgaagtat gcaacgagag cacttaataa cgatgagtta gaaaaagcag aaaaattaga 18660 acaagaaatt actgatttac gttctcaaat ccaagaaaaa caagaagaat tagataagct 18720 aaaagaaaaa gatggaactt cagaaaacaa tcaacaatca gtggaagtaa acgaagcacg 18780 tacttatcga aaccaagcaa acattaatga tttaggtatt tcgattcaaa acacaaaggt 18840 aacatcacaa gaagttagag attttactga atatcttgaa acacgcaatg atattcaagg 18900 tggttcgtta aaaacagact caggatttgt agttattcca gaggaaattg ttacagatat 18960 tttaaaatta aaagaggttg agtttaatct tgataagtat gtgacggtca aacgtgttac 19020 aaatggttct ggtaaatatc cggtagtacg acaatcagaa gttgcagccc ttgaaaaagt 19080 tgaagaatta gaagaaaacc ctgaattagc agttaaacca ttcttccaat tagcatatga 19140 cattaataca caccgtggtt acttccgaat ttcacgtgaa gcaatcgaag atgcaaaagt 19200 gaatgttttg caagaattga aactatggat ggcgcgaact attgcagcaa cacgaaacaa 19260 agcaattatt gatgttatca ctaaaggatc aacgggttct acaagttcag gttttgaaaa 19320 agaaggcaag aaattagaag ttaaaaaagc aaaatcttta gatgatatta aagatgctat 19380 taacctgaat gttaagccaa attacgaaca taatgttgcg attgtttcgc aaactatgtt 19440 tgcaaaatta gacaaaatga aagataagct aggaaactat ttaatccagc cagatgttaa 19500 agaaaaaacg caacagcgtt tattaggagc taaaatcgaa attttacctg atgaagtact 19560 agggcaaaaa ggtaataaca ctttgattat cggtaactta aaagatgcga ttgttttatt 19620 tgaccgctct caataccaag catcatggac tgactacatg catttcggag aatgtttaat 19680 gattgctgta cgtcaagact gtagaattct agattataaa tcagcaattg tgattgaata 19740 tgatgatagt gaacgcggtg aaggcgatct tggcttagaa gcataataag cgctcgatac 19800 tttataaaga ggtgataaac tatggcaatg tatgaagtga agaaatctta tactgacttg 19860 gaaaaaggcc agtatttaaa gtcaggtaaa cgtgttgaaa tgacagtaaa acgtgctgaa 19920 tatgttaaca aaaagctgaa agagcatgga gtaatacttg aaagagtaaa agaagaatag 19980 gtgattgaat gcaattaaca gctgaggaac ttaagttatt aaaaaagcat tgcaaaatag 20040 atcacaattc agaggacgac ttattagaaa tatattactc ttgggcattc catgaaatag 20100 ctagcgctgt tacggatgaa ccaagtaaat atattgattg gtttaaaagt catcctctat 20160 ttgctcgtgc tatataccct ttagcaagtt actattttga aaaccgtatt gcttatttgg 20220 atagggattt atcgcttgcg ccacatatgg ttttaagtac ggtgcataaa ttgagaggtt 20280 catttgagca atttttggag agtgaaaatg atgaaattta attccaataa attaaatgaa 20340 cgtatagatt tttgtgaaga tgtaagcgag agagtgaacg gaaatccgat gaaaccgaag 20400 acgaaaatat tatactcttg tttcgcttgc attcaagaat ctaaagaatc cgacactcaa 20460 acgaatctca atacaggtag caaattcatt aaaactatta ttatcagaga tacacgaggt 20520 gattataaac caacaaataa gcattacgtc ttgcatgaag ggcaaagatt taacatcaaa 20580 tatgtaaagc cagattatca agataaatct tatttgcgta tctatggcga ggtggtcatt 20640 taatgggggc aagaattgaa agtaataaca tcgaacaagg tttgaaaaat gcagttttaa 20700 aaatgaattt aaatagtaat gtaattgtca aagctggggc tatgtcatta gtcccgcttt 20760 taaaaagtaa tacacctttt gcgaatacta aaaagcatgc tcgcgatcac atagctgttt 20820 ctaatgtgaa aacagacaga cacacaagtg agaaaatcgt tacaattggt tacgctaaag 20880 gcgtctcaca tcgtattcat gcaacagaat ttggaacaat gtaccaaaaa ccacaattgt 20940 ttataacaaa aacagaaaag caagggaaaa acaaagtttt aaaaacaatg cttgatactg 21000 ctaagaggtt gcaaaaatga ttaatgttac caaattaatt agaaacgcta ttattgcaaa 21060 taacattaca gatgaagtga atgtgtttaa ctacactata gatgaccatt ttcacgaaaa 21120 aactgacaag cctattattc gtatatatcc cttaccgttc aatcctgaca catacgctga 21180 tgataacgag atttcaagag aataccatta ccaaattgat gtttggtggt ctcaagatga 21240 accgaacgag caagcagaaa aaattgttga gttactcaaa gtgataaatt ttcaatgtta 21300 ttacagagaa ccgttatacg agagtgacgt catgtcattc agacatatta taagagcaaa 21360 aggctcgatt ttatcaatga aattggagga aaattaaatg attgaaaaat tgaaacaagc 21420 accaagattt ttaaaattaa acttacaaca ttttgcagat acaggagttt cgggtatcgc 21480 aattggggta tcaaactttt attatgcacc tattttaaaa gatacagaaa atgaatggga 21540 aactggagct ggcacacgta ttcgtttctt aaaagaaatt gaagtagacc gtccacaaga 21600 taccgaggaa gattatgggg atgatatggt cgcagcaact gctgtatcta atggtaaact 21660 aagtgttaag acaacatttg ttactgttcc tgctgacgat aaggcgttct tgaatggcgc 21720 taaaaaaggt gtaggtggtt ataaatatgg agctaaggat atcccgccag atgtagcgat 21780 tgtatttgaa agacgtaatc atgatgagtc ttcagaatgg gttggcttgt tcaaaggtaa 21840 attcactcgt tcaagcatca aagggcaaac aaaacaagat aaagttgaat tccagaatga 21900 cgacgtagaa ggcaatttta ttgatcgttt gtttgatgag agctcgcatg ttactggcta 21960 tgataaaaaa ggaagcacta cagggcgcga ttatgtattc atggaaacat ttggtaaaac 22020 gaacctgtag gaaaaaaaca gaaaaagttg aagtcacttc tgtaaacgtc actgatgaac aagttacagt 22140 taaagttgat gctactaaac aactatcagc cacaaccgaa ccatctggac agaaagtaac 22200 ttatgcagtg actgaggggc aaacgtatgc tagcgtaaca tcaactggcc tcgttaaagg 22260 tttggcggaa ggtaatgcga ccgttacagc gactgcagga aagcaaactg atactgtgca 22320 aattacagta caatctaatt tagaaatgta agttttgagg gcttaacgcc ctctttttat 22380 tttggccaaa ttaaaaagaa agtaggaatt taataatgga acgtacatca attgaattaa 22440 ttacaggatt tacaaaaaca ggaaagccgc aatatcaaaa gtatttagcg aagccgatta 22500 ttactttgtt tgaaacaatt caaggttcaa aattaggttt gaaacttaac aaagccttta 22560 agggggctga ttttaaagat ctaacagaag aagaatttaa taacttaagt gtgacagaac 22620 aggaagaata caaaaacaag caagaagaat acgaaaacaa catggctgta caaatggaag 22680 tattagaaga agttttggat ttcatcgttg aagcttttga taatcaattt accagtatag 22740 aacttcaaaa aggattacca aatggtcaag aaggtattga aaagattgga cagttaattg 22800 gacgaattac aggtggggaa cctagcgata caaaaaagtt cgtgacagag aatcagaaat 22860 aagaaaagaa gatttaacac ctgaagctgt ctacaacaat tacaggaaaa tagctaaaga 22920 tttgatagaa aaaggcatgg atgcagaaaa agtggctaac atgccgatac acttcttttt 22980 agacattgtc gaatcgaaga ttgaaacaaa gcgaactgcg aaaagtttta aagatatttt 23040 ttaatcagcc tttaaaggtt gattttttat ttacatcttg gaagaaagga ggtttttaaa 23100 tgcctaatcc tataggtaat atggtcataa aggttgattt agatggttct ggattcaata 23160 gaggtgtgac aggtttaaat aggcaaatga aaatggtttc gcgtgagctt tcggctaatt 23220 tatcacaatt ttctagatat gataattcat tagaaaagtc gaagataaaa gtcgaaggtt 23280 tgagtaaaaa acaaaaagtt caagcccaga ttactaaaga gctgaaagat agttatgaca 23340 aacttagtaa agaaactggt gaaaacagtg caaagacaca agctgcggct gctaaataca 23400 atgaagctta cgctaaatta aaccaatatg agcgagagtt aaaccaagcc acacaagaat 23460 taaaagacat gcaaagagag cagaaagcat taaatactgc aatgggaaaa cttggtacca 23520 actttaataa ttttggtcct aaacttcaag aaattggtaa cagtatgaaa aatgtaggcc 23580 gtaacatgac tatgtatgta actgcgccgg tggttgctgg gtttgctgta gcagctaaaa 23640 aaggtattga attcgatgac agtatgagaa aagttaaagc aacttcaggt gctactgggg 23700 aagagtttga agctttgaag aaaaaggctc gcgaaatggg tgcaacaaca aaatttagtg 23760 catcagattc ggctgaagca ttaaattaca tggcacttgc tggttgggat tctaagcaaa 23820 tgatggaagg tttaagcgga gttatggatt tagcggcagc atctggcgaa gaactgggag 23880 cagtaagtga cattgttaca gatggactaa cggcatttgg tttaaaagca aaggatagtg 23940 gtcattttgc ggacgtttta gcacaaacta gctcgaaggc aaatacggat gttagagggc 24000 tcggagaagc ttttaaatat gtcgctcctg tagcaggtgc gttaggttac acgattgaag 24060 atacatctat tgcgataggt ttaatgagta atgctggtat caaaggtgaa aaagcaggta 24120 cagcgttacg aacaatgttc accaatcttt caagtccaac tagagctatg gggaatgaaa 24180 tggaacgctt aggaatatct attacagata gtaatgggaa aatgattcct atgcgaaagc 24240 ttttagacca actgagggaa aaatttaaac atctttcaaa agaccaacaa gctagttctg 24300 cagctacaat atttggtaaa gaagcgatgt caggagcatt agcgattata aatgcttctg 24360 atgaagacta tcaaaagtta accaaatcta tagattcatc taccggcgca tctaaaagaa 24420 tggccgatac aatggaatct ggtttaggtg ggaaattaag aactttaagg tcgcaattag 24480 aagaactagc cctaacgatt tatgacagaa tagaactagc actaaagatt atagtaagtg 24540 cttttagcaa agtagtgaca tgggttacta aattaccaac gtcaattcaa ttagcggttg 24600 ttgggtttgg attatttgta gcagttttag gtcctttagt ttttatgttc ggtttattta 24660 tcagcgtgat ggggaatgca atgacagttt taggaccctt gttaataaac gttaataaag 24720 ctagtggttt attcgcgttt ttaagaacta aaatcgcatc acttgttaaa ctatttccga 24780 ttttaggtgt gtcgatatca agtttaacgt tgcctataac attaattgta ggtgcattag 24840 ttggtattgg catagctttc tatcaagctt ataaacgttc agaaactttt agaaatattg 24900 taaatcaggc aatctctggt gtagcaaacg catttaaagc agctaaacta gcgttacaag 24960 gtttctttga tttattcaaa ggtgatagta aaggcgcggt taccctagag aagatatttc 25020 cacccgaaac tgtagcagga atacaaaatg tagttaatac gattagaaca actttcttta 25080 aagtagttga tgcaatcgtt ggtttcgcca aagagatagg cgctcaatta gcctctttct 25140 ggaaagagaa cggctcagaa ataacacaag ctttgcaaaa tatagctggt ttcattaaag 25200 caacctttga atttattttt aactttatta ttaaaccaat catgtttgcg atttggcaag 25260 tgatgcaatt tatttggccg gcggttaaag ctttgattgt cagcacttgg gaaaatatca 25320 aaggtgtaat acaaggggct attaatatta ttttgggtat tatcaaagtg ttctctagtc 25380 ttttcacagg aaactggcga ggcgtttggg acggcattgt aatgatactg aaaggtactg 25440 tgcagttaat ttggaattta atacaactgt ggtttatagg taaaattcta ggtgtagtga 25500 gatactttgg tggattactt aaaggtttaa taactattat atgggttgct ataataggcg 25560 ttttcaagaa atcattatcg gcaatttgga atgcaacaaa aagtattttt ggtttcttat 25620 tcaatagtgt taaatctatt ttcactaata tgaaaaactg gttatctagt acgtggaata 25680 atatcaaaag caataccgtc ggcaaggctc attcgttatt tacgggtgta aggtctaaat 25740 tcacaagttt atggaatgcg acgaaagata tatttactaa attaagaaat tggatgtcaa 25800 acatctggaa ctctattaaa gataacactg taggtatagc tggtcgctta tgggatagag 25860 tgcgtaacat ctttggaagc atgcgtgacg gtttaaaatc tatcattggt aaaattaaag 25920 atcatatcgg tggtatggta gacgctgtta aaagaggtct taataaatta attgaaggtt 25980 taaactgggt cggtggtaag ttgggtatgg acaaaatacc gaagttacac actggtactg 26040 aacatacgca tactactaca agattagtta agaacggtaa gattgcgcgg gatacgttcg 26100 ctacggttgg ggataaagga cgtggaaatg gtccgaatgg tttcagaaat gaaatgattg 26160 aattccctaa tggcaaacgg gtacttacgc ctaatacaga tacgacagcg tacttaccta 26220 aaggttcaaa agtatataac ggcgcacaaa cttattcaat gttaaatgga acgcttccaa 26280 gatttagcat aggtactatg tggaaagata ttaaatccgg tgcatcatcg gcatttaact 26340 ggacaaaaga tcaaataggt aaaggtacaa agtggcttgg cgataaagtt ggtgatgtca 26400 tggactttat cgataatcca ggcaaacttt taaattatgt acttcaagcg tttggagttg 26460 atttcagttc tctaactaaa ggtatgggta ttgctggcga tataacaaaa gctgcatggt 26520 ctaagattaa gaaaagtgca atcaagtggc ttgaggatgc tttcgcagag tcgggtgatg 26580 gcggtgtatt agatatgaat aaattacgtt acttatacgg tcacactgct gcttatacac 26640 ggaaaccgg acgcccattc catgaaggtc tggattttga ttacatttac gaacctgttc 26700 catcaaccat taatggtaga gcacaagtta tgccttttca taatggtggt tatggaaaat 26760 gggtgaaaat tgtaaagggc gccttagaag ttatttatgc acatttatct aaatataaag 26820 ttaaaactgg tcaacaagtt agggtcggcc agactgttgg tatatcgggg aatacggggt 26880 ttagtacagg acctcactta cattatgaga tgcgttggaa tggaagacat agagacccgt 26940 taccgtggtt aagaaagaat aatgggggcg gcaaaagtac acccggtggt aatggtgcag 27000 ctaatgctag acgagctatt aaggctgctc aaaatatttt aggaggaagg tataaggcga 27060 gttggattac taacgagatg atgcgtgttg cgagtcgtga atccaattat acagctaatg 27120 cagtcaataa ttgggatagc aacgcaagag ctggtatacc ttcaagaggt atgttccaaa 27180 tgatagatcc ttcatttaga gcgtacgcaa agtcgggtta caataatcct ctcaacccaa 27240 ctcatcaagc tatatcggct atgagatata ttgtgggtaa atgggtacca agaacaggct 27300 catggagagc tgcgttcaaa cgcgctggtg attacgcata tgctactggt ggcaaagtct 27360 ataacggatt gtaccactta ggggaagaag gatatccaga gtggataata cctactgatc 27420 caagtagagc gaacgaagca cacaaattat tagctttagc tgctaacgat attgataacc 27480 gctctaaaaa taagcgacca aacaacttac caaatccaag tataagtaat agtgatacaa 27540 actatattca tacattggag aataaactgg atgcggttat taattgtttg gttagtttgg 27600 ttgagtctaa tcaagttatt gcagataagg attacgaacc agttattaat aagtatgtgt 27660 ttgaagatga ggtaaataat tctatcgata aacgagagcg tcacgaatct acaagagtta 27720 gatttagaag aggaggcacg ataatctaat gcaagataca attcaaatag acaataaaac 27780 cattgaatgg ttagttgtac aaagagggtt tgagataccc tcttttaatt ttgttactga 27840 aaaagaaagt gtgaaaggta gaacaggttc tattgctaaa gctcgttatc taaatgatat 27900 cgaatttgaa ttacctctaa taattagaaa tgaagtcttg gcgccaggtg gacaaaaaac 27960 gcatgacgat atattggaag agttagttga attttttgat attgacaatt taaagccgaa 28020 aaaacttaaa ttcaaatctc aaaactggta ttggtttgca tactttgatg gaccattaaa 28080 attaccgaaa aacccaagag gttcagtgaa gttcactatc aaagtagtac taacagaccc 28140 ttacaaatat tcagtaacag gaaataaaaa tactgcgatt tcagaccaag tttcagttgt 28200 aaatagtggg actgctgaca ctcctttaat tgttgaagcc cgagcaatta aaccatctag 28260 ttactttatg atcactaaaa atgatgaaga ttattttatg gttggtgatg atgaggtaac 28320 caaagaagtt aaggattaca tgcctcctgt ttatcatagt gagtttcgtg atttcaaagg 28380 ttggactaag atgattactg aagatattcc aagtaatgat ttaggtggta aggtcggcgg 28440 tgactttgtg atatccaatc ttggcgaagg atataaagca actaattttc ctgatgcaaa 28500 aggttgggtt ggtgctggca cgaaacgagg gctccctaaa gcgatgacag attttcaaat 28560 tacctataaa tgtattgttg aacaaaaagg taaaggtgcc ggaagaacag cacaacatat 28620 ttatgatagt gatggtaagt tacttgcttc tattggttat gaaaataaat atcatgatag 28680 aaaaatagga catattgttg ttacgttgta taaccaaaaa ggagacccca aaaagatata 28740 cgactatcag aataaaccga taatgtataa cttggacaga atcgttgttt atatgcggct 28800 cagaagagta ggtaataaat tttctattaa aacttggaaa tttgatcaca ttaaagaccc 28860 agatagacgt aaacctattg atatggatga gaaagagtgg atagatggcg gtaagtttta 28920 tcagcgtcca gcttctatca tagctatcta tagtgcgaag tataacggtt ataagtggat 28980 ggagatgaat ggattaggtt cattcaatac ggagattcta ccgaaaccga aaggcgcaag 29040 ggatgtcatt atacaaaaag gtgatttagt gaaaatagat atgcaagcaa aaagtgttgt 29100 catcaatgag gaaccaatgt tgagcgagaa atcgtttgga agtaattatt tcaatgttga 29160 ttctgggtac agtgaattaa tcatacaacc tgaaaacgtc tttgatacga cggttaaatg 29220 gcaagataga tatttataga aaggagatga gagtgtgata catgttttag attttaacga 29280 caagattata gatttccttt ctactgatga cccttcctta gttagagga ttcataaacg 29340 taatgttaat gacaattcag aaatgcttga actgctcata tcatcagaaa gagctgaaaa 29400 gttccgtgaa cgacatcgtg ttattataag ggattcaaac aaacaatggc gtgaatttat 29460 tattaactgg gttcaagata cgatggacgg ctacacagag atagaatgta tagcgtctta 29520 tcttgctgat ataacaca ctaaaccgta tgcaccaggc aaatttgaga aaaagataac 29580 ttcagaagca ttgaaagatg tgttgagtga tacaggttgg gaagtttctg aacaaaccga 29640 atacgatggc ttacgtacta cgtcatggac ttcttatcaa actagatatg aagttttaaa 29700 gcaattatgt acaacctata aaatggtatt ggatttttat atagagctta gttctaatac 29760 cgtcaaaggt agatatgtgg tactcaaaaa gaaaaacagc ttattcaaag gtaaagaaat 29820 tgagtatggt aaagatttgg ttgggttaac taggaagatt gatatgtcag aaatcaaaac 29880 agcattaatt gctgtgggac ccgaaaacga caaaggaaag cgtttagagt tagttgtgac 29940 agatgacgaa gcacaaagtc aattcaactt acctacccgt tatatttggg gaatatacga 30000 acctcaatca gatgatcaaa atatgaatga aacacggttg cgttctttag ccaaaacaga 30060 gttaaataaa cgtaagtcgg cagttatgtc atatgagatt acttctactg atttggaagt 30120 tacgatatccg cacgagatta tatcaattgg tgatacagtc agagtaaaac atagagattt 30180 taacccgcca ttgtatgtag aggcagaagt tattgccgaa gaatataaca taatttcaga 30240 aaatagcaca tatacattcg gtcaacctaa agagttcaaa gaatcagaat tacgagaaga 30300 gtttaacaag cgattgaaca taatacatca aaagttaaac gataatatta gcaatatcaa 30360 cactatagta aaagatgttg tagatagtga attagaatac tttgaacgca aaatacacaa 30420 aagtgataca ccgccagaaa atccagtcaa tgatatgctt tggtatgata caagtaaccc 30480 tgatgttgct gtcttgcgta gatattggaa tggtcgatgg attgaagaaa caccaaatga 30540 tgttgaaaaa ttaggtggta taacaagaga gaaagcgcta ttcagtgaat taaacaatat 30600 atttattaat ttatctatac aacacgctag tcttttgtca gaagctacag aattactgaa 30660 tagcgagtac ttagtagata atgatttgaa agcggactta caagcaagtt tagacgctgt 30720 gattgatgtt tataatcaaa ttaaaaataa tttagaatct atgacacccg aaactgcaac 30780 gattggtcgg ttggtagata caaaaacttt atttcttgag tatagaaaga aattacaaga 30840 tgtttataca gatgtagaag atgtcaaaat cgccatttca gatagattta aattattaca 30900 gtcacaatac actgatgaaa aatataaaga agcgttggaa ataatagcaa caaaatttgg 30960 tttaacggtg aatgaagatt tgcagttagt cggagaacct aatgttgtta aatcagctat 31020 tgaagcagct agagaatcca caaaagaaca attacgtgac tatgtaaaaa catcggacta 31080 taaaacagac aaagacggta ttgttgaacg tttagatact gctgaagctg agagaacgac 31140 tttaaaaggt gaaatcaaag ataaagttac gttaaacgaa tatcgaaacg gattggaaga 31200 acaaaaacaa tatactgatg accagttaag tgatttgtcc aataatcctg agattaaagc 31260 aagtattgaa caagcaaatc aagaagcgca agaagcttta aaatcataca ttgatgctca 31320 agatgatctt aaagagaagg aatcgcaagc gtatgctgat ggtaaaattt cggaagaaga 31380 gcaacgcgct atacaagatg ctcaagctaa acttgaagag gcaaaacaaa acgcagaact 31440 aaaggctaga aacgctgaaa agaaagctaa tgcttataca gacaacaagg tcaaagaaag 31500 cacagatgca cagaggaaaa cattgactcg ctatggttct caaattatac aaaatggtaa 31560 ggaaatcaaa ttaagaacta caaaagaaga gtttaatgct tctaaaagaa cactatcaag 31620 agtgttagca gacatcactg taaatgctat gaaaggcatc tatttaaggt atgacgaaaa 31680 tggggcgatt acttcacata ctattgataa agatggcgtg aaaattagtg gcgataaagt 31740 tgatataaca gcgaatagag aatttaatgt agtcgcaaat aatattaata acaaagttgg 31800 taaaaatgac attgttaata gcctaaactt atcaaatgaa ggtcttgaca tcaatgtgaa 31860 tagaattggt attaaaggcg gaaatgctaa ccgttatgta caagttcaaa atgattttat 31920 tgaacttggc ggaatcgtac aacgaacttg gaaaggcaaa cgatcaaccg atgatatatt 31980 cacacgtctt aaagatggac atctaaggtt tagaaataat accgcaggcg gttcacttta 32040 tatgtcacat tttggtattt caacatatat tgatggagaa ggcgaagacg gaggttcatc 32100 cggtactatt caatggtggg ataaaactta cagtgatagc ggtatgaatg gcataacaat 32160 caattcttat ggcggtgtag tcgctttaac atctgactac aaccgaatta ttatcgattc 32220 atatgcttca gctaatattg aaagtagaga agcaccgata tatttatctc cgaacaccaa 32280 aaataaacct ggtttaaacc gattcgcatt cacattatca aacgctgata gtgcatacga 32340 aactgacggt tatatcatgt ttggttcaga tgaaaactat aagtacggtg ctggattaag 32400 attttctaaa cgtagcaata aaggattggt tcaagtcgtt aatggtgact atgctacagg 32460 cggagacact acaattgagt caggtatggg caaattcaac ttagttaaac gaagagatgg 32520 aaatagttac gttagcattc aaagttatga tttattggcg gtaggttctg ataatgctgg 32580 cgatagagtc gcttctaatt ctatttataa gcgtacttat tcagcacctg ctaacttaca 32640 cattacttct gctggaacaa ttgggcgtgc tacttctgcc aaaaagtata aaatttcaat 32700 cgaaaatcaa tatatcaatg aagacgatca gttcagtcat tcaaaagaga ttttaaagct 32760 tccaattcgt acatggtttg acaaatatga atcggaaata atggctaaag aattggaaag 32820 tggtaaaaag ttatctgatg atacttttaa acttagtcga catactggct taatagcgga 32880 agaggttgaa gaattaggat ttaatgaatt tgttatttat gatgacaacg gagaaatcga 32940 aggtatcgca tacgatagac tttgggttca tttaatacct attattaaaa accagcaatc 33000 aaaaatcgaa aaactggagg aattaataaa tgaatgatag caatcaaggt ttacaagcca 33060 atccacaata tacaattcac tatttatcgc aagaaatcac aagactaaca caagaaaatg 33120 caatgttaaa agcatatata caagaacaaa atgaaaaaag caaaagtgct gaggaagagt 33180 aatccttggc actattttta tacaaaaatt taaggaggtc atttaatatg gcaaatgaaa 33240 ttatcaaaaa aacagagaga tttattttag tacaaattga caaagaggga acagagcgcg 33300 ttttgtatca agattttgta ggcagtttta caacgtccga ttcagcaagt tatgcacaag 33360 attttaaatc tgaggaaaac gctaaaaaga ttgctgaaac tttaaatctt ttatatcaat 33420 taacaggcaa tcaaaacggt gtgaaagttg tgaaagaagt tgtggataga actgacttgt 33480 catctgataa atcagttgat agcgaaataa tgtaactata ctaagttatg agcattacgc 33540 tcatagcttt cttagaaagt aggtgtagtt ttggatgata ttcagaaaat aaaaaaagag 33600 ctttctgaat tagttgaacg tgttgatgat gttgaaatac tagcaaacga aacagctgat 33660 catgtgcttg aacttagaga ggaacataag caacatcata atgaactaag agaatctcat 33720 aaagaactta aagataagca agataaagtt gtagatgaga atttagagca aacaaagata 33780 ttaaacagaa ttgaagaaag atatcaaacg caagtagatg ttgcgcaaaa aaatgaagaa 33840 aagacactcg cccaaaataa atggctcgta ggtgccatat gggcgcttgt aacaattgtt 33900 atgattgcag tcattactgc atcaattact gcgttattac cttaagggag gtggacataa 33960 tgagttgggc aagatggttg tcatgttatt tgtatggtcg taaatgtaaa taatgttttt 34020 ggtcagtgca tcggcactgg ctttttattt attgttgtaa ttatggtaat atgcagaagt 34080 gagcaagttg gatagatggt ggctatctga gtataaggag gtggtgccta tgttggcatt 34140 actgaaatct ttagaaagga gatgcctaat gattacaatt agtaccatgt tgcagtttgg 34200 tttattcctt attgcattga taggtctagt aatcaagctt attgaattaa gcaataaaaa 34260 ataaccatcg ctaactttgg ctggtttcga tggttaaatg gttattaatt taatctttaa 34320 tctaaaatag ccaccgtctt tttaacgggc tcattagggt aacatgtttg cgcatgttgc 34380 cctttttcta tatataaatt aacacaccat aatataaata tcaaatagac ggcttattag 34440 tcgtcttttt attttgggta aaaggagata agaatatgat taattggaaa attagaatga 34500 aacaaaaatc attttgggta gcgatattgt cagctatctt tttatttgct caaaacatcg 34560 caaaagctat tgggtatgat atccaagttt atacagagca attaacagac ggtttaaacg 34620 ctatattagg atttttagta ttaactggtg tgattcaaga cccgactact aaaggtatag 34680 gtgatagcca ccaagcttta gaatatgaag aaccaagaag aaaatactag 34730

Claims (14)

포도상구균에 특이적인 사멸능을 갖는, 서열번호 1로 표시되는 염기서열로 이루어진 박테리오파지 SA7.
Bacteriophage SA7 consisting of the nucleotide sequence shown in SEQ ID NO: 1, which has the killing activity specific for staphylococci.
제1항에 있어서, 상기 박테리오파지는 수탁번호 KFCC11673P인, 박테리오파지 SA7.
2. The bacteriophage according to claim 1, wherein the bacteriophage is the accession number KFCC 11673P.
제1항에 있어서, 상기 포도상구균은 황색포도상구균(Staphylococcus aureus)인 것을 특징으로 하는, 박테리오파지 SA7.
The bacteriophage SA7 according to claim 1, wherein the staphylococcus is Staphylococcus aureus .
제1항의 박테리오파지 SA7을 포함하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료용 약학적 조성물.
A pharmaceutical composition for preventing or treating infectious diseases caused by Staphylococcus aureus comprising the bacteriophage SA7 of claim 1.
제4항에 있어서, 상기 포도상구균은 황색포도상구균(Staphylococcus aureus)인 것을 특징으로 하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료용 약학적 조성물.
The pharmaceutical composition according to claim 4, wherein the staphylococcus is Staphylococcus aureus . The pharmaceutical composition for preventing or treating infectious diseases caused by Staphylococcus aureus.
제5항에 있어서, 상기 황색포도상구균은 항생제 내성 황색포도상구균인 것을 특징으로 하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료용 약학적 조성물.
The pharmaceutical composition according to claim 5, wherein the Staphylococcus aureus is an antibiotic-resistant Staphylococcus aureus.
제6항에 있어서, 상기 항생제 내성 황색포도상구균은 메티실린 내성 황색포도상구균, 리팜피신 내성 황색포도상구균, 이소니아지드 내성 황색포도상구균, 가나마이신 내성 황색포도상구균, 페니실린 내성 황색포도상구균 또는 반코마이신 내성 황색포도상구균인 것을 특징으로 하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료용 약학적 조성물.
The antibiotic-resistant Staphylococcus aureus according to claim 6, wherein the antibiotic-resistant Staphylococcus aureus is selected from the group consisting of methicillin-resistant Staphylococcus aureus, rifampicin-resistant Staphylococcus aureus, isoniazid-resistant Staphylococcus aureus, kanamycin-resistant Staphylococcus aureus, penicillin-resistant Staphylococcus aureus or vancomycin- Or a pharmaceutically acceptable salt thereof. The pharmaceutical composition for preventing or treating an infectious disease caused by Staphylococcus aureus.
제4항에 있어서, 상기 포도상구균에 의한 감염성 질병은 유방염, 피부염, 패혈증, 화농성 질환, 식중독, 폐렴, 골수염, 농가진, 균혈증, 심내막염, 여드름, 수막염, 골관절염, 피부감염, 장염 및 요로감염으로 구성된 군으로부터 선택되는 것을 특징으로 하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료용 약학적 조성물.
5. The method according to claim 4, wherein the infectious disease caused by Staphylococcus aureus is selected from the group consisting of mastitis, dermatitis, sepsis, pyogenic disease, food poisoning, pneumonia, osteomyelitis, impetigo, bacteremia, endocarditis, acne, meningitis, osteoarthritis, skin infection, Lt; RTI ID = 0.0 &gt; of Staphylococcus aureus &lt; / RTI &gt;
제1항의 박테리오파지 SA7을 포함하는, 항생용 조성물.
An antibiotic composition comprising the bacteriophage SA7 of claim 1.
제1항의 박테리오파지 SA7을 포함하는, 사료 첨가용 조성물.
A composition for feed addition comprising the bacteriophage SA7 of claim 1.
제10항의 사료 첨가용 조성물을 포함하는, 사료.
A feed comprising the feed additive composition of claim 10.
제1항의 박테리오파지 SA7을 포함하는, 소독제.
A disinfectant comprising bacteriophage SA7 of claim 1.
제1항의 박테리오파지 SA7을 포함하는, 세척제.
A cleaning agent comprising bacteriophage SA7 of claim 1.
제1항의 박테리오파지 SA7을 개체에 투여하는 단계를 포함하는, 포도상구균에 의한 감염성 질병의 예방 또는 치료 방법.
A method for preventing or treating an infectious disease caused by staphylococci, comprising the step of administering the bacteriophage SA7 of claim 1 to a subject.
KR1020160135293A 2016-10-18 2016-10-18 Novel Staphylococcus specific bacteriophage SA7 and antibacterial composition comprising the same KR20180042748A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109082414A (en) * 2018-06-29 2018-12-25 浙江工业大学 A kind of staphylococcus aureus bacteriophage and application
KR20220043584A (en) * 2020-09-29 2022-04-05 주식회사 옵티팜 Novel Staphylococcus specific bacteriophage OPT-SC01 and antibacterial composition comprising the same
KR102418861B1 (en) * 2021-12-15 2022-07-08 주식회사 마이크로진 Bacteriophage with growth inhibition activity against Staphylococcus sp.
WO2023140723A1 (en) * 2022-01-21 2023-07-27 서울여자대학교 산학협력단 Bacteriophage kmsp1 specific to staphylococcus bacteria and antibacterial composition comprising same

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109082414A (en) * 2018-06-29 2018-12-25 浙江工业大学 A kind of staphylococcus aureus bacteriophage and application
KR20220043584A (en) * 2020-09-29 2022-04-05 주식회사 옵티팜 Novel Staphylococcus specific bacteriophage OPT-SC01 and antibacterial composition comprising the same
WO2022071718A1 (en) * 2020-09-29 2022-04-07 주식회사 옵티팜 Novel bacteriophage opt-sc01 specific to staphylococcus bacteria and antibacterial composition comprising same
KR102418861B1 (en) * 2021-12-15 2022-07-08 주식회사 마이크로진 Bacteriophage with growth inhibition activity against Staphylococcus sp.
WO2023140723A1 (en) * 2022-01-21 2023-07-27 서울여자대학교 산학협력단 Bacteriophage kmsp1 specific to staphylococcus bacteria and antibacterial composition comprising same

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