Abstract
ABSTRACTMGE1 encodes a yeast chaperone involved in Fe-S cluster metabolism and protein import into the mitochondria. In this study, we identified MGE1 as a multicopy suppressor of susceptibility to the antifungal fluconazole in the model yeast Saccharomyces cerevisiae. We demonstrate that this phenomenon is not exclusively dependent on the integrity of the mitochondrial DNA or on the presence of the drug efflux pump Pdr5. Instead, we show that the increased dosage of Mge1 plays a protective role by retaining increased amounts of ergosterol upon fluconazole treatment. Iron metabolism and, more particularly, Fe-S cluster formation are involved in regulating this process, since the responsible Hsp70 chaperone, Ssq1, is required. Additionally, we show the necessity but, by itself, insufficiency of activating the iron regulon in establishing the Mge1-related effect on drug susceptibility. Finally, we confirm a similar role for Mge1 in fluconazole susceptibility in the pathogenic fungi Candida glabrata and Candida albicans.
Highlights
MGE1 encodes a yeast chaperone involved in Fe-S cluster metabolism and protein import into the mitochondria
We showed earlier that iron metabolism is involved in regulating susceptibility to fluconazole, since addition of the iron chelator doxycycline to fluconazole-treated Candida albicans and S. cerevisiae cells reduces or even completely abolishes tolerance [7, 27]
Aiming to identify new regulators of fluconazole susceptibility, we performed a screening of BY4742 transformed with multicopy plasmids, containing parts of the S. cerevisiae genomic library obtained from F
Summary
MGE1 encodes a yeast chaperone involved in Fe-S cluster metabolism and protein import into the mitochondria. The fungus can, obtain certain transient, metabolic or epigenetic, adaptations that confer decreased susceptibility to the antifungal agent This slow residual growth at inhibitory concentrations of the drug is called tolerance or trailing growth and hypothetically generates the time needed for and the possibility of directional selection promoting the acquirement of alterations in the genome, causing resistance [7, 8]. We show that overexpressing the orthologues of MGE1 in the pathogenic fungi C. glabrata and C. albicans affects fluconazole susceptibility in a similar way As such, elucidating this apparently conserved fungal mechanism may yield interesting new targets for drug development
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