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Virulence. 2018;9(1):1150-1162. doi: 10.1080/21505594.2018.1475798.

Biguanides enhance antifungal activity against Candida glabrata.

Author information

1
a Division of Infectious Disease , Massachusetts General Hospital , Boston , MA , USA.
2
b Biomedical Engineering and Biotechnology , University of Massachusetts Medical School , Worcester , MA , USA.
3
c Division of Pulmonary and Critical Care , Massachusetts General Hospital , Boston , MA , USA.
4
d Department of Internal Medicine , Harvard Medical School , Boston , MA , USA.
5
e Deparment of Pharmacy , Massachusetts General Hospital , Boston , MA , USA.
6
f Diabetes Unit, Department of Endocrinology , Massachusetts General Hospital , Boston , MA , USA.
7
g Center for Human Genetic Research , Massachusetts General Hospital , Boston , MA , USA.
8
h Center for Regenerative Medicine , Massachusetts General Hospital , Boston , MA , USA.

Abstract

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.

KEYWORDS:

Candida; Candida glabrata; biguanide; drug resistance; metformin; minimum inhibitory concentration (MIC)

PMID:
29962263
PMCID:
PMC6086317
DOI:
10.1080/21505594.2018.1475798
[Indexed for MEDLINE]
Free PMC Article

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