Sterol-C4-methyl-oxidase Erg251 governs Candida albicans hypoxic growth, commensalism and virulence

Intestinal-colonizing Candida albicans is a primary source of systemic infection where it translocates across intestinal barriers into the bloodstream leading to disseminated candidiasis. To persist in the gastrointestinal tract, C. albicans must adapt to complex environments, including extreme hypoxic conditions (EHC). Here, we performed a functional genomic screen to identify genes important for C. albicans fitness under EHC. We discovered that one of the two C. albicans sterol C4-methyl oxidases, Erg251, is specifically required for producing ergosterol, an essential component for fungal membrane, in low oxygen conditions. Deleting Erg251 or mutating key amino acid residues for its function under EHC impaired C. albicans virulence and colonization in mouse models of systemic infection and commensalism, respectively. Selective inhibitors of fungal sterol C4-methyl oxidases, inhibit C. albicans growth in vitro and in a nematode infection model, showing therapeutic potential.