This application requests support for a program in which fungal isolates from several selected environmental niche groups will be explored as sources of new bioactive natural products. This program will employ a unique ecology- and taxonomy-based approach to organism selection that represents a significant departure from traditional random microbial screening programs. Fungi targeted for investigation include isolates from freshwater, fungicolous, coprophilous, sclerotium-producing, and endophytic communities. These ecosystems have been chosen on the basis of a variety of considerations, including high incidence of interspecies antagonism, morphological, taxonomic, and ecological distinctiveness, and track record of productivity. Based on the increasing need for new treatments to combat opportunistic fungal infections, in house efforts will focus on a search for new antifungal metabolites. Extracts and compounds will also be tested for other activities through an arrangement with the Screening Technologies Branch of the NCI Developmental Therapeutics Program. The proposed project involves a collaboration between the Prs group and that of Prof. C.A. Shearer, one of the world's foremost experts in aquatic mycology. Dr. D.T. Wicklow, a colleague with extensive and complimentary expertise in other aspects of mycology, will also participate. With the aid of prior support from NIH and other sources, studies of isolates from these ecosystems have already afforded a variety of new bioactive agents, including many with novel structures. These results provide strong evidence that this general approach is effective, and demonstrate the ability of the research team to perform the proposed studies. Many isolates and extracts are available for immediate investigation. In many instances, there are no literature reports of prior chemical studies of the corresponding organisms. Extracts of solid-substrate fermentation cultures of individual fungal isolates will be subjected to biological assays to prioritize them for study. Active components will be isolated through bioassay-guided fractionation, and their structures will be determined using spectroscopic methods. While chemical studies progress, further species will be isolated and screened, thereby providing a continuing stream of new isolates for investigation. [unreadable] [unreadable]