CN116672457A - Application of pharmaceutical composition in preparation of candida albicans resistant medicines - Google Patents
Application of pharmaceutical composition in preparation of candida albicans resistant medicines Download PDFInfo
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- CN116672457A CN116672457A CN202310663676.8A CN202310663676A CN116672457A CN 116672457 A CN116672457 A CN 116672457A CN 202310663676 A CN202310663676 A CN 202310663676A CN 116672457 A CN116672457 A CN 116672457A
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- candida albicans
- antifungal agent
- pharmaceutical composition
- dp44mt
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- 241000222122 Candida albicans Species 0.000 title claims abstract description 35
- 229940095731 candida albicans Drugs 0.000 title claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 239000003814 drug Substances 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 7
- 229940079593 drug Drugs 0.000 title description 17
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 34
- 239000003429 antifungal agent Substances 0.000 claims abstract description 29
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims abstract description 22
- XOBIGRNRXCAMJQ-UHFFFAOYSA-N 3-(dipyridin-2-ylmethylideneamino)-1,1-dimethylthiourea Chemical compound C=1C=CC=NC=1C(=NNC(=S)N(C)C)C1=CC=CC=N1 XOBIGRNRXCAMJQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 206010007134 Candida infections Diseases 0.000 claims abstract description 12
- 201000003984 candidiasis Diseases 0.000 claims abstract description 10
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 8
- 150000004291 polyenes Chemical class 0.000 claims abstract description 8
- 230000001032 anti-candidal effect Effects 0.000 claims abstract description 7
- 108010049047 Echinocandins Proteins 0.000 claims abstract description 6
- 238000011282 treatment Methods 0.000 claims abstract description 5
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229960004413 flucytosine Drugs 0.000 claims abstract description 3
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 claims description 12
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims description 12
- 229960003942 amphotericin b Drugs 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 229960000988 nystatin Drugs 0.000 claims description 4
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 claims description 4
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims description 3
- 229960004884 fluconazole Drugs 0.000 claims description 3
- 239000006186 oral dosage form Substances 0.000 claims description 3
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 2
- 108010064760 Anidulafungin Proteins 0.000 claims description 2
- 108010020326 Caspofungin Proteins 0.000 claims description 2
- 201000004624 Dermatitis Diseases 0.000 claims description 2
- 208000005577 Gastroenteritis Diseases 0.000 claims description 2
- 201000009906 Meningitis Diseases 0.000 claims description 2
- 108010021062 Micafungin Proteins 0.000 claims description 2
- 208000007027 Oral Candidiasis Diseases 0.000 claims description 2
- 206010034016 Paronychia Diseases 0.000 claims description 2
- 241000029132 Paronychia Species 0.000 claims description 2
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- 241000287411 Turdidae Species 0.000 claims description 2
- 206010046914 Vaginal infection Diseases 0.000 claims description 2
- 229960003348 anidulafungin Drugs 0.000 claims description 2
- JHVAMHSQVVQIOT-MFAJLEFUSA-N anidulafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@@H](C)O)[C@H](O)[C@@H](O)C=2C=CC(O)=CC=2)[C@@H](C)O)=O)C=C1 JHVAMHSQVVQIOT-MFAJLEFUSA-N 0.000 claims description 2
- 229960003034 caspofungin Drugs 0.000 claims description 2
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 claims description 2
- 206010014599 encephalitis Diseases 0.000 claims description 2
- 206010014665 endocarditis Diseases 0.000 claims description 2
- 229960004130 itraconazole Drugs 0.000 claims description 2
- 229960002159 micafungin Drugs 0.000 claims description 2
- PIEUQSKUWLMALL-YABMTYFHSA-N micafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS(O)(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 PIEUQSKUWLMALL-YABMTYFHSA-N 0.000 claims description 2
- 229960001589 posaconazole Drugs 0.000 claims description 2
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 claims description 2
- 230000009278 visceral effect Effects 0.000 claims description 2
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 claims description 2
- 229960004740 voriconazole Drugs 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims 2
- 208000005035 cutaneous candidiasis Diseases 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
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- 230000000694 effects Effects 0.000 abstract description 12
- 238000002474 experimental method Methods 0.000 abstract description 11
- 206010059866 Drug resistance Diseases 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
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- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 210000005099 mouse brain capillary cell Anatomy 0.000 description 12
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- 239000012980 RPMI-1640 medium Substances 0.000 description 3
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- 102000004169 proteins and genes Human genes 0.000 description 3
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- RXGJTUSBYWCRBK-UHFFFAOYSA-M 5-methylphenazinium methyl sulfate Chemical compound COS([O-])(=O)=O.C1=CC=C2[N+](C)=C(C=CC=C3)C3=NC2=C1 RXGJTUSBYWCRBK-UHFFFAOYSA-M 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
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- 238000000034 method Methods 0.000 description 2
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- 229910052618 mica group Inorganic materials 0.000 description 2
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- -1 small molecule compounds Chemical class 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000003260 vortexing Methods 0.000 description 2
- CFBVWCHTNQHZLT-UHFFFAOYSA-N 4-methoxy-5-[3-(2-methoxy-4-nitro-5-sulfophenyl)-5-(phenylcarbamoyl)tetrazol-3-ium-2-yl]-2-nitrobenzenesulfonate Chemical compound COC1=CC([N+]([O-])=O)=C(S([O-])(=O)=O)C=C1N1[N+](C=2C(=CC(=C(C=2)S(O)(=O)=O)[N+]([O-])=O)OC)=NC(C(=O)NC=2C=CC=CC=2)=N1 CFBVWCHTNQHZLT-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
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- 101150106008 ERG11 gene Proteins 0.000 description 1
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- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
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- 206010042938 Systemic candida Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 230000008686 ergosterol biosynthesis Effects 0.000 description 1
- 150000002137 ergosterols Chemical class 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61P31/10—Antimycotics
-
- 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
Abstract
The invention provides an anti-candida albicans pharmaceutical composition, which comprises Dp44mT and an antifungal agent; the antifungal agent is selected from one or more of azole antifungal agent, polyene antifungal agent, echinocandin antifungal agent and flucytosine. According to the invention, through chessboard experiments, dp44mT can enhance the anti-biofilm formation effect of the common antifungal agent, and enhance the mature biofilm destruction effect of the common antifungal agent, so that the antifungal effect of the common antifungal agent is enhanced, and the formation of candida albicans drug resistance is reduced, thereby laying a theoretical foundation for a new treatment mode of candidiasis.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of a pharmaceutical composition in preparation of an anti-candida albicans drug.
Background
Candida albicans is a fungus, and causes diseases when the immunity of the human body is low, and can cause shallow and deep infection and even threaten life. It is estimated that over 25 ten thousand patients develop invasive candidiasis annually worldwide with mortality rates of over 40%. Although more than 100 candida species have been found, candida albicans is still considered the most common conditionally pathogenic species, 80% of candida infections are associated with candida albicans, which accounts for about 19% of infections in intensive care units. Thus, candida albicans infection often places a heavy burden on society and economy.
At present, medicines for treating candida albicans are mainly azole medicines and polyene medicines, however, the medicines have the defects of narrow antibacterial spectrum, large toxicity and side effects and the like to different degrees; in addition, the phenomenon of drug resistance of candida albicans is more and more prominent with the long-term and large-scale use of antifungal drugs. The emergence of resistance to candida albicans may be associated with the following causes:
(1) Altering the target molecule: changing the structure of the target protein reduces the drug sensitivity or over-expresses the target protein, thereby causing the drug to fail, such as the mutation of ERG11 gene causes the amino acid sequence of the azole drug target enzyme to change, thereby disabling the azole drug.
(2) Reduction of intracellular drug content: by reducing cell permeability or enhancing cell membrane efflux pump activity, thereby reducing intracellular drug content, such as reduced cytosine permease activity in candida albicans cells, absorption of 5-FC can be reduced, resulting in the development of drug resistance.
(3) Altering metabolic pathways: fungi can increase resistance to drugs by altering metabolic pathways, such as resistance to polyenes, primarily by depleting ergosterols through loss of function mutations in the ergosterol biosynthesis genes, thereby producing alternative sterols that do not interact efficiently with polyenes and therefore have reduced sensitivity to antimycotics.
(4) Cell wall adaptation changes: the Fks1 protein is a catalytic subunit of the glucan synthase complex, and the coding gene thereof is mutated, which is likely to lead to reduced sensitivity to echinocandin.
(5) Formation of candida albicans biofilm: candida albicans biofilm can reduce the entry of drugs into cells, thereby increasing resistance to commonly used antifungal drugs (e.g., fluconazole).
Although the mechanism of drug resistance of candida albicans is known at present, methods for enhancing antifungal effect or reversing drug resistance by influencing the drug resistance mechanism based on the original antifungal are few. Therefore, the enhancement of the antifungal effect of common antifungal agents by exploring novel small molecule compounds, thereby achieving the effect of improving the treatment of candida albicans infection, is an effective means for resisting candida albicans at present.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides application of a pharmaceutical composition in preparing an anti-candida albicans medicament.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a first aspect of the invention provides an anti-candida albicans pharmaceutical composition comprising Dp44mT and an antifungal agent; the antifungal agent is selected from one or more of azole antifungal agent, polyene antifungal agent, echinocandin antifungal agent and flucytosine.
Further, the azole antifungal agent is one or more selected from fluconazole, voriconazole, posaconazole and itraconazole.
Further, the polyene antifungal agent is amphotericin B and/or nystatin.
Further, the echinocandin antifungal agent is selected from one or more of caspofungin, micafungin and anidulafungin.
In a second aspect, the invention provides the use of the above pharmaceutical composition for the preparation of an anti-candida albicans medicament.
In a third aspect, the present invention provides the use of the above pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of diseases caused by candida albicans.
Further, the disease caused by candida albicans is skin candidiasis, mucosal candidiasis or visceral and central nervous candidiasis.
Further, the disease caused by candida albicans is selected from skin inflammation, paronychia, perianal inflammation, inguinal inflammation, colpitis, angular inflammation, thrush, pneumonia caused by candida albicans, gastroenteritis, endocarditis, meningitis and encephalitis.
Further, the dosage form of the medicine is an external dosage form, an injection dosage form or an oral dosage form.
Compared with the prior art, the invention has the following technical effects:
according to the invention, through chessboard experiments, dp44mT can enhance the anti-biofilm formation effect of the common antifungal agent, and enhance the mature biofilm destruction effect of the common antifungal agent, so that the antifungal effect of the common antifungal agent is enhanced, and the formation of candida albicans drug resistance is reduced, thereby laying a theoretical foundation for a new treatment mode of candidiasis.
Detailed Description
The present invention will be described in detail and in detail by way of the following examples, which are not intended to limit the scope of the invention, for better understanding of the invention.
The methods described in the examples are carried out using conventional methods, if not specified, and the reagents used are, if not specified, conventional commercially available reagents or reagents formulated by conventional methods.
Example 1
This example demonstrates that Dp44mT can enhance the anti-biofilm formation of commonly used antifungals, with the following experimental steps and results:
1. biofilm formation checkerboard experiment
After washing activated candida albicans three times with PBS, the bacterial solution is diluted to 1X 10 by using RPMI1640 culture medium 6 CFU/mL, then plated into 96-well plates with 200. Mu.L per well. Then, the 96-well plate was placed in a constant temperature incubator at 37℃for culturing for 90min, and the plate was designated as an adhesion stage. After 90min of incubation, the 96-well plates were removed, the supernatant was discarded, washed once with sterile PBS, then RPMI1640 medium without or with reagents was added, incubated at 37℃for 24 hours in a constant temperature incubator, and the incubation phase was defined.
Biofilm formation checkerboard experiment: mixed reagents of different concentrations are added during the proliferation phase of biofilm formation.
(1) Chessboard experiments with Dp44mT and Amphotericin B (AMP): dp44mT concentration is 2 μg/mL to 0.008 μg/mL and AMP concentration is 4 μg/mL to 0.0625 μg/mL.
(2) Chessboard experiments with Dp44mT and Nystatin (Nystatin, NYS): dp44mT concentration is 2 μg/mL to 0.008 μg/mL and NYS concentration is 8 μg/mL to 0.125 μg/mL.
(3) Chessboard experiment of Dp44mT and azoles: dp44mT concentration is 2 μg/mL to 0.03125 μg/mL, and azole concentration is 64 μg/mL to 0.25 μg/mL.
Xtt reduction experiments
The 2,3-Bis (2-Methoxy-4-Nitro-5-Sulfophenyl) -2H-tetrazole-5-carboxyanilide (2, 3-Bis- (2-Methoxy-4-Nitro-5-Sulfophenyl) -2H-Tetrazolium-5-Carboxanilide, XTT) assay is a colorimetric method to detect metabolic activity by measuring the reduction of Tetrazolium salt reagent XTT. Fresh 0.5mg/mLXTT and 0.32mg/mL phenazine methosulfate (Phenazine methosulfate, PMS) were prepared half an hour before the biofilm incubation time reached 24 hours, mixed in a 9:1 ratio after vortexing well, then vortexing well and placed protected from light. When the biofilm incubation time reached 24 hours, the media was discarded, then washed three times with PBS to remove the media, then 100. Mu. LXTT-PMS mix was added to each well and incubated at 37℃for 2 hours in the absence of light. After 2 hours, OD was measured 450 . The lowest reagent concentration when the OD value became 20% or less of the original was noted as the lowest biofilm formation inhibitory concentration (Minimum biofilm inhibitory concentration, MBIC).
3. Calculation of fractional inhibitory concentration index (Fractional inhibitory concentration index, FICI)
The interaction FICI model between the two reagents was analyzed. The FICI is calculated as: fici=ficia+ficib, wherein the FICIA is calculated as MICA sheet/MICA association and the FICIB is calculated as MICB sheet/MICB association. MIC (MIC) (reagent sheet) MBIC or MBEC, MIC when reagents alone (reagent Union) MBIC or MBEC when combined with the agent. Wherein, FICI is less than or equal to 0.5 and is synergistic; FICI is more than 0.5 and less than or equal to 1 and is added; FICI < 1 < 4 is no interaction; FICI is greater than or equal to 4.
The results are shown in Table 1 below, MBIC (AMP sheet) MBIC at 2. Mu.g/mL (AMP Union) MBIC at 0.5 μg/mL (Dp 44mT Single) MBIC at 1. Mu.g/mL (Dp 44mT Union) FICI is 0.258 at 0.008 μg/mL, thus providing a synergistic effect. MBIC (Membrane biological Integrated Circuit) (NYS sheet) MBIC at 8 μg/mL (NYS Union) MBIC at 4. Mu.g/mL (Dp 44mT Single) MBIC at 1. Mu.g/mL (Dp 44mT Union) The FICI is 1 at 0.5. Mu.g/mL, and thus has additive effect. MBIC (Membrane biological Integrated Circuit) (azole monomer) MBIC is greater than 64 μg/mL (azole series) MBIC at 0.25 μg/mL (Dp 44mT Single) MBIC at 1. Mu.g/mL (Dp 44mT Union) At 0.5 μg/mL, FICI is 0.503, thus having additive interactions.
TABLE 1 interaction of Dp44mT with antimycotic drug against Candida albicans biofilm formation
Example 2
This example demonstrates that Dp44mT can enhance the mature biofilm disruption effect of commonly used antifungals, with the following experimental steps and results:
after Candida albicans was cultured at 37℃for 24 hours to form a biofilm, the medium was discarded, and then washed three times with PBS, as described above. The prepared RPMI1640 medium containing reagents with different concentrations or no reagent is added into the holes containing the biological film, and then the culture is carried out for 24 hours at the constant temperature of 37 ℃.
(1) Chessboard experiments of Dp44mT and AMP: dp44mT concentration is 256 μg/mL to 1 μg/mL and AMP concentration is 4 μg/mL to 0.0625 μg/mL.
(2) Chessboard experiments of Dp44mT and NYS: dp44mT concentration was 256 μg/mL to 1 μg/mL and NYS concentration was 64 μg/mL to 1 μg/mL.
XTT reduction experiments were used as a determination reagent to determine the lowest biofilm disruption concentration (Minimum biofilm eradication concentration, MBEC) that disrupted candida albicans mature biofilm, and then a fractional inhibition concentration index was calculated.
The results are shown in Table 2 below, MBEC (AMP sheet) MBEC at 4 μg/mL (AMP Union) MBEC at 0.5 μg/mL (Dp 44mT Single) Greater than 256 μg/mL MBEC (Dp 44mT Union) At 128 μg/mL, FICI is 0.375, thus AMP and Dp44mT have the effect of synergistically increasing disruption of mature biofilm. MBEC (MBEC) (NYS sheet) MBEC at 8 μg/mL (NYS Union) MBEC at 2 μg/mL (Dp 44mT Single) Greater than 256 μg/mL MBEC (Dp 44mT Union) At 128 μg/mL, FICI is 0.5, thus NYS and Dp44mT also have the effect of synergistically increasing disruption of mature biofilm.
TABLE 2 interaction of Dp44mT with antifungal agents to disrupt Candida albicans mature biofilm
The above description of the specific embodiments of the present invention has been given by way of example only, and the present invention is not limited to the above described specific embodiments. It will be apparent to those skilled in the art that any equivalent modifications and substitutions of the present invention are intended to be within the scope of the present invention. Accordingly, equivalent changes and modifications are intended to be included within the scope of the present invention without departing from the spirit and scope thereof.
Claims (10)
1. An anti-candida albicans pharmaceutical composition comprising Dp44mT and an antifungal agent; the antifungal agent is selected from one or more of azole antifungal agent, polyene antifungal agent, echinocandin antifungal agent and flucytosine.
2. The pharmaceutical composition according to claim 1, wherein the azole antifungal is selected from one or more of fluconazole, voriconazole, posaconazole, itraconazole.
3. The pharmaceutical composition according to claim 1, wherein the polyene antifungal agent is amphotericin B and/or nystatin.
4. The pharmaceutical composition of claim 1, wherein the echinocandin antifungal agent is selected from one or more of caspofungin, micafungin, and anidulafungin.
5. Use of a pharmaceutical composition according to any one of claims 1-4 for the preparation of an anti-candida albicans medicament.
6. The use according to claim 5, wherein the medicament is in the form of a topical, injectable or oral dosage form.
7. Use of a pharmaceutical composition according to any one of claims 1 to 4 for the preparation of a medicament for the prophylaxis and/or treatment of diseases caused by candida albicans.
8. The use according to claim 7, wherein the disease caused by candida albicans is cutaneous candidiasis, mucosal candidiasis or visceral and central nervous candidiasis.
9. The use according to claim 7, wherein the disease caused by candida albicans is selected from the group consisting of skin inflammation, paronychia, perianal inflammation, inguinal inflammation, colpitis, stomatitis, thrush, candida albicans-induced pneumonia, gastroenteritis, endocarditis, meningitis and encephalitis.
10. The use according to claim 7, wherein the medicament is in the form of a topical, injectable or oral dosage form.
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