. Current treatments for fungal infections are limited to a few therapeutic options, primarily amphotericin B which interacts with membrane sterols and azoles which inhibit membrane-sterol biosynthesis. Unfortunately, amphotericin B is toxic to humans and clinical resistance to azoles is increasing. These observations underscore the need for new antifungals. The identification of bioactive compounds is becoming increasingly more difficult. Many potential sources have been screened numerous times. One way to avoid this stumbling block is to identify unique organisms that have not been investigated. The long-term goal of this project is the identification of novel antifungal agents which act through fungal- specific mechanisms. In this Phase II proposal, the PI plans to extend Phase I work and screen an additional 2500 extracts from marine organisms for antifungal activity using an integrated and streamlined battery of whole-cell and mechanism-based in vitro assays. From the 1000 samples screened in Phase I and the additional 2500 samples to be screened in Phase II approximately 50 samples will be selected from which the active fungal component will be purified. The structures of the purified compounds will be determined and eight purified compounds will be tested for in vivo efficacy using several fungal infection models.
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