Biomaterial Database

Biguanides enhance antifungal activity against Candida glabrata. 2018

Shuying Xu, and Marianela Feliu, and Allison K Lord, and Daniel P Lukason, and Paige E Negoro, and Nida S Khan, and Zeina Dagher, and Michael B Feldman, and Jennifer L Reedy, and Samantha N Steiger, and Jenny M Tam, and Alexander A Soukas, and David B Sykes, and Michael K Mansour

a Division of Infectious Disease , Massachusetts General Hospital , Boston , MA , USA.

Candida spp. are the fourth leading cause of nosocomial blood stream infections in North America. Candida glabrata is the second most frequently isolated species, and rapid development of antifungal resistance has made treatment a challenge. In this study, we investigate the therapeutic potential of metformin, a biguanide with well-established action for diabetes, as an antifungal agent against C. glabrata. Both wild type and antifungal-resistant isolates of C. glabrata were subjected to biguanide and biguanide-antifungal combination treatment. Metformin, as well as other members of the biguanide family, were found to have antifungal activity against C. glabrata, with MIC50 of 9.34 ± 0.16 mg/mL, 2.09 ± 0.04 mg/mL and 1.87 ± 0.05 mg/mL for metformin, phenformin and buformin, respectively. We demonstrate that biguanides enhance the activity of several antifungal drugs, including voriconazole, fluconazole, and amphotericin, but not micafungin. The biguanide-antifungal combinations allowed for additional antifungal effects, with fraction inhibition concentration indexes ranging from 0.5 to 1. Furthermore, metformin was able to lower antifungal MIC50 in voriconazole and fluconazole-resistant clinical isolates of C. glabrata. We also observed growth reduction of C. glabrata with rapamycin and an FIC of 0.84 ± 0.09 when combined with metformin, suggesting biguanide action in C. glabrata may be related to inhibition of the mTOR complex. We conclude that the biguanide class has direct antifungal therapeutic potential and enhances the activity of select antifungals in the treatment of resistant C. glabrata isolates. These data support the further investigation of biguanides in the combination treatment of serious fungal infections.

UI	MeSH Term	Description	Entries
D008687	Metformin	A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. (From Martindale, The Extra Pharmacopoeia, 30th ed, p289)	Dimethylguanylguanidine,Dimethylbiguanidine,Glucophage,Metformin HCl,Metformin Hydrochloride,HCl, Metformin,Hydrochloride, Metformin
D008826	Microbial Sensitivity Tests	Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses).	Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D009181	Mycoses	Diseases caused by FUNGI.	Fungus Diseases,Fungal Diseases,Fungal Infections,Fungus Infections,Disease, Fungal,Disease, Fungus,Diseases, Fungal,Diseases, Fungus,Fungal Disease,Fungal Infection,Fungus Disease,Fungus Infection,Infection, Fungal,Infection, Fungus,Infections, Fungal,Infections, Fungus
D002175	Candida	A genus of yeast-like mitosporic Saccharomycetales fungi characterized by producing yeast cells, mycelia, pseudomycelia, and blastophores. It is commonly part of the normal flora of the skin, mouth, intestinal tract, and vagina, but can cause a variety of infections, including CANDIDIASIS; ONYCHOMYCOSIS; VULVOVAGINAL CANDIDIASIS; and CANDIDIASIS, ORAL (THRUSH).	Candida guilliermondii var. nitratophila,Candida utilis,Cyberlindnera jadinii,Hansenula jadinii,Lindnera jadinii,Monilia,Pichia jadinii,Saccharomyces jadinii,Torula utilis,Torulopsis utilis,Monilias
D004338	Drug Combinations	Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture.	Drug Combination,Combination, Drug,Combinations, Drug
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077551	Micafungin	A cyclic lipo-hexapeptide echinocandin antifungal agent that is used for the treatment and prevention of CANDIDIASIS.	FK 463,FK-463,FK463,Micafungin Sodium,Mycamine
D000666	Amphotericin B	Macrolide antifungal antibiotic produced by Streptomyces nodosus obtained from soil of the Orinoco river region of Venezuela.	Amphocil,Amphotericin,Amphotericin B Cholesterol Dispersion,Amphotericin B Colloidal Dispersion,Fungizone
D000935	Antifungal Agents	Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues.	Anti-Fungal Agents,Antifungal Agent,Fungicides, Therapeutic,Antibiotics, Antifungal,Therapeutic Fungicides,Agent, Antifungal,Anti Fungal Agents,Antifungal Antibiotics
D001645	Biguanides	Derivatives of biguanide (the structure formula HN(C(NH)NH2)2) that are primarily used as oral HYPOGLYCEMIC AGENTS for the treatment of DIABETES MELLITUS, TYPE 2 and PREDIABETES.	Biguanide