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Synergistic antifungal effect of glabridin and fluconazole.

ABSTRACT: The incidence of invasive fungal infections is increasing in recent years. The present study mainly investigated glabridin (Gla) alone and especially in combination with fluconazole (FLC) against Cryptococcus neoformans and Candida species (Candida albicans, Candida tropicalis, Candida krusei, Candida parapsilosis and Candida Glabratas) by different methods. The minimal inhibitory concentration (MIC) and the minimal fungicidal concentration (MFC) indicated that Gla possessed a broad-spectrum antifungal activity at relatively high concentrations. After combining with FLC, Gla exerted a potent synergistic effect against drug-resistant C. albicans and C. tropicalis at lower concentrations when interpreted by fractional inhibitory concentration index (FICI). Disk diffusion test and time-killing test confirming the synergistic fungicidal effect. Cell growth tests suggested that the synergistic effect of the two drugs depended more on the concentration of Gla. The cell envelop damage including a significant decrease of cell size and membrane permeability increasing were found after Gla treatment. Together, our results suggested that Gla possessed a synergistic effect with FLC and the cell envelope damage maybe contributed to the synergistic effect, which providing new information for developing novel antifungal agents.

SUBMITTER: Liu W

PROVIDER: S-EPMC4110026 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Synergistic antifungal effect of glabridin and fluconazole.

Liu Wei W Li Li Ping LP Zhang Jun Dong JD Li Qun Q Shen Hui H Chen Si Min SM He Li Juan LJ Yan Lan L Xu Guo Tong GT An Mao Mao MM Jiang Yuan Ying YY

PloS one 20140724 7

The incidence of invasive fungal infections is increasing in recent years. The present study mainly investigated glabridin (Gla) alone and especially in combination with fluconazole (FLC) against Cryptococcus neoformans and Candida species (Candida albicans, Candida tropicalis, Candida krusei, Candida parapsilosis and Candida Glabratas) by different methods. The minimal inhibitory concentration (MIC) and the minimal fungicidal concentration (MFC) indicated that Gla possessed a broad-spectrum ant ...[more]

PMID: 25058485

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Project description:Fungal diseases have become a major public health issue worldwide. Increasing drug resistance and the limited number of available antifungals result in high morbidity and mortality. Metal-based drugs have been reported to be therapeutic agents against major protozoan diseases, but knowledge of their ability to function as antifungals is limited. In this study, we found that calcium supplementation combined with iron deficiency causes dramatic growth inhibition of the human fungal pathogens Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Calcium induces the downregulation of iron uptake-related genes and, in particular, causes a decrease in the expression of the transcription factor HapX, which tends to transcriptionally activate siderophore-mediated iron acquisition under iron-deficient conditions. Iron deficiency causes calcium overload and the overproduction of intracellular reactive oxygen species (ROS), and perturbed ion homeostasis suppresses fungal growth. These phenomena are consistently identified in azole-resistant A. fumigatus isolates. The findings here imply that low iron availability lets cells mistakenly absorb calcium as a substitute, causing calcium abnormalities. Thus, there is a mutual effect between iron and calcium in fungal pathogens, and the combination of calcium with an iron chelator could serve to improve antifungal therapy. IMPORTANCE Millions of immunocompromised people are at a higher risk of developing different types of severe fungal diseases. The limited number of antifungals and the emergence of antimicrobial resistance highlight an urgent need for new strategies against invasive fungal infections. Here, we report that calcium can interfere with iron absorption of fungal pathogens, especially in iron-limited environments. Thus, a combination of calcium supplementation with an iron chelator inhibits the growth of human fungal pathogens, including Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Moreover, we demonstrate that iron deficiency induces a nonspecific calcium uptake response, which results in toxic levels of metal. Findings in this study suggest that a microenvironment with excess calcium and limited iron is an efficient strategy to curb the growth of fungal pathogens, especially for drug-resistant isolates.

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Synergistic antifungal effect of glabridin and fluconazole.

Publications

Synergistic antifungal effect of glabridin and fluconazole.

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