Determining Antifungal Target Sites in the Sterol Pathway of the Yeasts Candida and Saccharomyces

Fungal infections continue to be a growing problem in present day health care. Part of this trend is due to advanced medical treatments that either allow entry of opportunistic pathogens or suppress the normal immune response. Disease states which diminish the immune response are also contributors. This situation is exacerbated by the increased incidence of resistance to the current arsenal of antifungal drugs. Thus, there is a pressing need for the discovery and development of new antifungal compounds. The research supported by this award seeks to identify new fungal sites against which novel classes of antifungals would be effective. Targeted in this work are unexplored steps in ergosterol biosynthesis in the human pathogen, Candida albicans. Initial identification of essential sterol biosynthetic steps were performed in Saccharomyces cerevisiae. Three genes, ERG25, ERG26, and ERG27, encoding the enzymes for sterol demethylation at C-4, have been characterized in these two organisms and been found to be excellent targets for antifungal development. A fourth gene, ERG6, encoding the C-24 transmethylase, has also been investigated and found to be potentially effective site for inhibition based on impaired membrane function of cells unable to perform this reaction.