application): While the incidence of fungal infections has escalated significantly, only a limited number of antifungal drugs are currently available for treatment. For this reason, the ultimate objective of the proposed investigation is to identify novel lead compounds for the development of antifungal drugs. To accomplish their goals, the applicants propose five specific aims, namely: (1) exploring novel targets already validated as essential for growth and/or infectivity of Candida albicans in the host, including fatty acid synthase (Fas2p), histidine kinase (Cahk1p), and glucan transferases (Phr1p/Phr2p). In addition, the investigators plan to screen natural product libraries by developing high throughput assays libraries against these targets for discovery and characterization of novel antifungal agents. (2) validating other potential targets for which the corresponding genes have already been obtained, including a second histidine kinase (Cassk1p), and the putative transcriptional/translational regulators, Elf2p and Mot2p. (3) using bioassay-directed fractionation to isolate and purify active constituents from active extracts and determine the structures of purified active compounds, as well as to prioritize active compounds. (4) characterizing pure compounds in in vitro assays in order to determine potency, selectivity, activity spectrum, etc., and prioritize promising leads for further study. (5) determining in vivo efficacy of appropriate compounds in animal models of systemic candidiasis. If efficacious, compounds will also be evaluated in an animal model of aspergillosis. The targets chosen for study are considered to be attractive because either no human homologues are known to exist or because they are readily distinguishable biochemically from the human homologue. The investigation outlined in the application will combine and integrate the complementing strengths of researchers at the Georgetown University (molecular biology/target development, animal models), the University of Mississippi National Center for Development of Natural Products (natural products chemistry/antifungal screening), and Dorlin Pharmaceuticals Inc. (assay development, high throughput screening).
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