This proposal requests support to modify and expand an ongoing investigation of the natural products chemsitry pf coprophilous fungi. These rarely-studied fungi are ecologically, morphologically and taxonomically distinctive, and they commonly display antagonistic effects against ohter fungi. Our search for antifungal metabolites from these species is based on a systematic, ecology-based approach to microrganism selection that represents a departure from traditional random microbial screening programs. A variety of new antifungal agents, including many with unusual chemical structures, have been isolated in this project through bioassay-guided chemical studies of coprophilous fungi. OUr results provide compelling evidence that these fungi show considerable promise as sources of novel anifungal natual products. Because of the increasingly urgent need for the new treatment effective against opportunistic fungal infection in humans, screening efforst will focus exclusively on searches for new metabolites with activity against medically relevant fungi. Pure compounds will ultimately be tested for other activities, with high priority assigned to cancer-relevant assays. Many additional isolates that exhibit anitfungal effects against opportunistic fungal pathogens in direct competition assays are available for investigation, and none of these have been studied chemically. THese isolates will be cultivated under both liquid and sole-substrate fermentation conditions, and the extracts frm these fermentations will be tested against a panel of medical fungal isolates to prioritize cultures for chemical studies. Antifungal components will be isolated through bioassay-guided fractionation, and their structures will determined using state-of -of-the-art spectroscopic techniques. While chemical studies are in progress, further coprophilous species will be isolated,identified, and screened for antifungal activity in laboratory of Prof. D. Malloch, an expert in thea field of coprophilous mycology. The progress achieved in this project thus far demonstrates the ability of the research team to perform the proposed studies, and underscores the need for continiued investigation of this relatively unexplored source of potentially valuable natural products.
