MECHANISM OF ACTION OF NOVEL ANTIFUNGAL COMPOUNDS

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The most common AIDS-related fungal Ol are cryptococcosis and candidiasis. The toxicities, lack of efficacy, and development of resistance to existing antifungal agents mandate the need for new therapies. The overall goals of this project are (a) to investigate the mechanism(s) of action of selected prototype fungicidal natural products and (b) to identify and characterize molecular targets with potential for the design of new therapies, including the development of in vitro assay systems that will be useful in the discovery of new therapeutic and prophylactic treatments for AIDS-related fungal Oi. To meet these overall objectives, the following specific aims will be pursued; 1. Evaluate the effects(s) of the selected lead compounds on general biochemical processes i the susceptible yeast cells. 2. Evaluate the interaction of the selected prototype antifungal compounds with the targets of known antifungal agents, i.e., chitin synthetase, glucan synthase, ergosterol binding, ergosterol biosynthesis, protein synthesis, or mannan binding. 3. Evaluate the effect(s) of the selected prototype compounds with other potential antifungal targets. i.e., topoisomerase I or II, DNA binding, polyamine synthesis and cell permeability. 4. For compounds that do not appear to act by a known mechanism, identify and characterize the molecular targets by use of molecular, thermodynamic, and biochemical properties. 5. Investigate the utility of a "reversal" in vitro assay system for the detection of novel antifungal agents that inhibit specific fungal targets (i.e., siderophore production, polyamine synthesis, production of secreted proteinases in C. albicans, polysaccharide capsule formation and melanin production in Cryptococcus neoformans).