JP5279054B2 - 抗菌剤 - Google Patents
抗菌剤 Download PDFInfo
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- JP5279054B2 JP5279054B2 JP2011524865A JP2011524865A JP5279054B2 JP 5279054 B2 JP5279054 B2 JP 5279054B2 JP 2011524865 A JP2011524865 A JP 2011524865A JP 2011524865 A JP2011524865 A JP 2011524865A JP 5279054 B2 JP5279054 B2 JP 5279054B2
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- antibacterial agent
- egcg
- acyl group
- agent according
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- 239000003242 anti bacterial agent Substances 0.000 title claims abstract description 83
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical class O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 claims abstract description 172
- 125000002252 acyl group Chemical group 0.000 claims abstract description 109
- 239000000126 substance Substances 0.000 claims abstract description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
- 125000001424 substituent group Chemical group 0.000 claims abstract description 14
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 10
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 10
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- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006150 trypticase soy agar Substances 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
- A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Zoology (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Environmental Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Dentistry (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
R1〜R6は、それぞれ、水素原子、ハロゲン、ナトリウム、カリウムまたは直鎖もしくは分枝状の飽和もしくは不飽和アシル基であり、同一でも異なっていても良く、前記アシル基は、さらに1または複数の置換基で置換されていても良く、前記R1〜R6の少なくとも1つが前記アシル基であり、R7〜R16は、それぞれ、水素原子、ハロゲン、ナトリウムまたはカリウムであり、同一でも異なっていても良い。ナトリウムまたはカリウムは、その他の一価金属またはアルカリ金属であってもよい。
(1)分子量35,000、等電点4.10
例えば、Aspergillus niger由来リパーゼ
(2)分子量64,000、等電点4.30、80℃10分間の処理で不活性化
例えば、Candida rugosa由来リパーゼ
(3)至適pH8、至適温度60℃、pH4〜10の範囲で特に安定、70℃以下で特に安定
例えば、Pseudomonas fluorescens由来リパーゼ
(4)分子量60,000、至適pH6〜7、pH安定性3〜8、至適温度40〜50℃、37℃以下において溶液状態で特に安定
例えば、Candida cylindracea由来リパーゼ、Candida rugosa由来リパーゼ
(5)分子量30,000、等電点4.5、至適pH8〜9.5、pH安定性7〜10、至適温度50℃、40℃以下において特に安定
例えば、Alcaligenes属由来リパーゼ
(6)分子量31,000、等電点4.9、至適pH7〜9、pH安定性6〜10、至適温度65〜70℃、50℃以下において特に安定
例えば、Alcaligenes属由来リパーゼ
(7)分子量31,000、等電点5.2、至適pH7〜9、pH安定性6〜10、至適温度65〜70℃、60℃以下において特に安定
例えば、Pseudomonas cepacia由来リパーゼ、Burkholderia cepacia由来リパーゼ
(8)分子量27,000、等電点6.6、至適pH7〜8、pH安定性6〜9、至適温度50℃、40℃以下において特に安定
例えば、Pseudomonas stutzeri由来リパーゼ
(1)EGCG誘導体の調製
下記方法によりEGCG誘導体を調製した。
No.1 EGCG−C8またはEGCG−octanonate
No.2 EGCG−C12またはEGCG−laurate
No.3 EGCG−C16またはEGCG−palmitate
No.4 EGCG−C18またはEGCG−stearate
No.5 EGCG−C20またはEGCG−eicosanoate
細菌として、Methicillin−susceptible Staphylococcus aureus(MSSA)NCTC8325およびMethicillin−resistant Staphylococcus aureus(MRSA)ATCC43300を使用した。前記各細菌の培養は、培地として、Mueller−Hinton Broth(MH−broth、Difco社製)を使用した。そして、各EGCG誘導体について、Clinical and Laboratory Standards Institute (CLSI)の微量液体希釈法に準拠して、最小発育阻止濃度(MIC:Minimum inhibitory concentration)を測定した(以下、同様)。
前記EGCG−C16について、MRSA ATCC43300、E.coli MG1655およびP.aeruginosa PAO1に対する殺菌効果を測定した。細菌の培養には、培地として、MH−brothを使用した。
(1)EGCG誘導体の調製
下記方法によりEGCG誘導体を調製した。
No.6 EGCG−C16またはEGCG−palmitate
No.7 EGCG−C8×2またはEGCG−dioctanoate
No.8 EGCG−C18またはEGCG−stearate
No.9 EGCG−C18EまたはEGCG−oleate
No.10 EGCG−C18DEまたはEGCG−linolate
No.11 EGCG−C18TEまたはEGCG−α−linoleate
No.12 EGCG−C16EまたはEGCG−palmitoleate
前記EGCG誘導体を、それぞれ、1280μg/mLとなるように、100%DMSOで溶解した。これらの溶液を、滅菌蒸留水で希釈し、抗菌剤溶液を調製した。そして、細菌として、MSSA NCTC8325、MSSA ATCC25923、MSSA ATCC12600、MSSA ATCC29213、MSSA臨床分離株5株(No.1〜No.5)、MRSA ATCC43300およびMRSA臨床分離株7株(No.6〜No.12)を用いた以外は、前記実施例1の(2)と同様にして、最小発育阻止濃度(MIC)を測定した。これらの結果を下記表6に示す。
EGCG−C16≦EGCG−C16E
EGCG−C18≦EGCG−C18E<EGCG−C18DE≦
EGCG−C18TE
EGCG−C16≦EGCG−C8×2
下記表7および表8に示す各種標準菌株について、前記実施例2の抗菌剤溶液を使用し、以下に示す以外は、前記実施例1の(2)と同様にして、MICを測定した。前記抗菌剤溶液は、100%DMSOに溶解後、滅菌蒸留水で希釈して調製した。前記各種菌株は、それぞれ、ATCCまたはNCTC由来の菌株を用いた。Moraxella catarrhalisおよびAspergillus fumigatusは、獲得耐性機構を持たない臨床分離株を用いた。富栄養菌であるStreptococcus pneumoniae ATCC49619、Streptococcus pyogenes ATCC19615、Streptococcus agalactiae ATCC13813、Moraxella catarrhalis、およびHaemophilis influenzae ATCC49766に対しては、培地にストレプト・ヘモサプリメント(栄研化学社製)を加えた。真菌に対するMIC測定は、RPMI1640/MOPS(pH7.0)培地を用い、CLSI法に準じ、微量液体希釈法により行った。約2×103cells/mLの真菌を接種し、35℃、24〜48時間培養後、MICを判定した。また、前記比較例2の抗菌剤溶液についても、同様にMICを測定した。
EGCG−C16について、MSSAおよびMRSAに対する抗菌作用が、細胞壁構成成分であるペプチドグリカン(PG)、D−Ala−D−Ala、または外膜のリポポリサッカライド(LPS)の添加によって抑制されるかを確認した。MICの測定は、前記実施例2の(2)に準じて行った。
EGCG−C16について、MSSAおよびMRSAの膜構造に対する障害性を確認した。
EGCG誘導体について、Escherichia coli MG1655に対する抗菌力における多剤排出ポンプの影響を検討した。
前記EGCG誘導体として、前記実施例2のEGCG−C16、C8×2、C16EおよびC18TEを用いた。
前記EGCG誘導体を用い、前記細菌として、Escherichia coli MG1655(以下、野生型株という)および前記Escherichia coli MG1655の遺伝子欠損株を用いた以外は、前記実施例2の(2)と同様にして、最小発育阻止濃度(MIC)を測定した。前記遺伝子欠損株は、前記Escherichia coli MG1655における排出ポンプ遺伝子acrB、acrDまたはacrEFを欠損させた株(△acrD、△acrEFおよび△acrB)、前記排出ポンプ遺伝子のコードタンパク質と共役する外膜タンパクの遺伝子tolCを欠損させた株(△tolC)を用いた。
前記EGCG−C16について、チェッカーボード法により、β−ラクタム薬であるアンピシリン(ABPC)またはイミペネム(IPM)との併用による、ブドウ球菌に対する抗菌性を確認した。
D環にアシル基を有するEGCG誘導体と、B環にアシル基を有するEGCG誘導体について、代謝安定性を確認した。
Claims (19)
- R1〜R6において、前記アシル基の主鎖長が、原子数2〜20である、請求項1記載の抗菌剤。
- R1〜R6において、前記アシル基の炭素原子数が、2〜20である、請求項1または2記載の抗菌剤。
- R1〜R6において、前記置換基が、アルキル基、アミノ基、アルキルアミノ基およびジアルキルアミノ基からなる群から選択される少なくとも一つである、請求項1から3のいずれか一項に記載の抗菌剤。
- R1〜R6において、
前記アルキル基が、炭素原子数1〜6の直鎖もしくは分枝アルキル基であり、
前記アルキルアミノ基におけるアルキル基が、炭素原子数1〜6の直鎖もしくは分枝アルキル基であり、
前記ジアルキルアミノ基におけるアルキル基が、炭素原子数1〜6の直鎖もしくは分枝アルキル基であり、
R1〜R6は、それぞれ、同一でも異なっていても良い、請求項4記載の抗菌剤。 - R1〜R6において、
前記アルキル基がメチル基であり、前記アルキルアミノ基がメチルアミノ基であり、
前記ジアルキルアミノ基がジメチルアミノ基であり、
R1〜R6は、それぞれ、同一でも異なっていても良い、請求項4または5記載の抗菌剤。 - R1、R2、R5およびR6の少なくとも一つが、前記アシル基である、請求項1から6のいずれか一項に記載の抗菌剤。
- R1、R2、R5およびR6の少なくとも一つが、前記アシル基であり、その他が、水素原子である、請求項1から7のいずれか一項に記載の抗菌剤。
- R7〜R16が、水素原子である、請求項1から8のいずれか一項に記載の抗菌剤。
- 前記アシル基の主鎖長が、原子数12〜18である、請求項1から9のいずれか一項に記載の抗菌剤。
- 前記アシル基の炭素原子数が、12〜18である、請求項1から10のいずれか一項に記載の抗菌剤。
- 前記アシル基が、直鎖飽和アシル基および直鎖不飽和アシル基の少なくとも一方である、請求項1から11のいずれか一項に記載の抗菌剤。
- 前記アシル基が、ブチリル基、オクタノイル基、トランス−8−メチル−6−ノネノイル基、ゲラノイル基、ラウロイル基、12−(ジメチルアミノ)ラウロイル基、ファルネソイル基、パルミトイル基、パルミトレイル基、ステアロイル基、オレオイル基、リノレイル基、リノレニル基、エイコサノイル基およびそれらの異性体からなる群から選択された少なくとも一つのアシル基である、請求項1から12のいずれか一項に記載の抗菌剤。
- 前記抗菌剤が、ブドウ球菌、肺炎球菌、緑膿菌、キャンピロバクター、ピロリ菌、大腸菌およびレジオネラ菌からなる群から選択された少なくとも一つの菌に対する抗菌剤である、請求項1から13のいずれか一項に記載の抗菌剤。
- 前記化学式(1)において、前記R1〜R6のいずれか1つが、炭素数16または18の不飽和アシル基である、請求項1から11、および14のいずれか一項に記載の抗菌剤。
- 前記炭素数16の不飽和アシル基が、パルミトイル基である、請求項15記載の抗菌剤。
- 前記炭素数18の不飽和アシル基が、オレオイル基、リノレイル基またはリノレニル基である、請求項15記載の抗菌剤。
- 前記化学式(1)において、前記R1〜R6のいずれか2つが、炭素数8の飽和アシル基である、請求項1から9、および14のいずれか一項に記載の抗菌剤。
- 菌の感染を抑制する方法であって、
非ヒト動物に請求項1から18のいずれか一項に記載の抗菌剤を投与することを特徴とする感染抑制方法。
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CN106822265A (zh) * | 2017-04-01 | 2017-06-13 | 杨涵 | 一种治疗人***瘤病毒感染的环保型抗菌灭活剂 |
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