This proposal requests support to continue and expand an investigation of the natural products chemistry of coprophilous fungi. These rarely- studied fungi are ecologically, morphologically, and taxonomically distinctive, and they commonly display antagonistic effects against other fungi. Based on these considerations, and on initial positive results, coprophilous fungi show considerable promise as sources of new antifungal natural products. Compounds of this nature could be useful in the development of new treatments for fungal diseases in humans. Studies carried out in the first 2.5 years of this project have afforded several types of new antifungal agents, some of which possess unusual chemical structures. Many additional organisms that display inhibitory effects on medically relevant fungi are already available for chemical investigation. While studies of these organisms are in progress, further coprophilous species will be isolated, identified, and prescreened for antifungal activity in the laboratory of an expert in coprophilous mycology (Prof. D. Malloch). The types of fungi to be targeted are those considered most likely to exhibit antagonistic activity towards competitors, and will be selected on the basis of knowledge about their ecology and taxonomy. Isolates found to display antifungal effects will be grown in liquid culture, and extracts will be tested in-house and at a cooperating pharmaceutical company (Lilly) to prioritize cultures for chemical studies. Antifungal components will be isolated through on-site bioassay-guided fractionation, and their structures will be determined using state-of-the-art spectroscopic techniques. Antifungal potency of new metabolites will be further evaluated at Lilly. Pure compounds will also be tested for other important activities, with next priority given to cancer-relevant assays. The project has several unique aspects. The specific targeting of coprophilous fungi as sources of antifungals is unprecedented. None of the isolates to be included in this work (and few members of the genera they represent) have ever been studied chemically. The proposed approach relies upon knowledge of the ecology, taxonomy, and/or novelty of the organism prior to chemical investigation, thereby simplifying dereplication, increasing the odds of discovering new chemistry, and preventing repetitive investigation of heavily studied species. This systematic, ecology-based approach to microorganism selection represents a departure from traditional random microbial screening programs by attempting to introduce rationale at the beginning of the process. The progress made to date demonstrates the ability of the research team to perform the proposes studies, and underscores the need for continued investigation of this relatively unexplored source of potentially valuable natural products.
