Acquired immune deficiency syndrome (AIDS) is propagated by the human immunodeficiency virus (HIV). Iinfected patients frequently succumb to opportunistic fungal infections as a result of reduced immunocompetence. Amphotericin B has been used effectively against disseminated mycoses caused by agents such as Candida albicans, however, toxic side effects preclude more general use. Common use of the recently approved azole antifungal agent Fluconazole has been accompanied by significant clinical emergence of non-albicans candidiasis (eg. Candida glabrata, C. Krusei) and the increasing appearance of Fluconazole-resistant C. Albicans strains in AIDS patients, and the clinic, in general. Clearly new antifungal agents are needed to meet the challenges of these emerging pathogens. Marine invertebrates, in particular sponges, produce a diverse array of chemical compounds including a relatively unexplored antifungal agents. This program seeks to discover novel antifungal leads that exhibit activity against important emerging pathogenic fungi from chemical diverse marine invertebrates. Organisms will be collected and screened for antifungal activity against pathogens relevant to AIDS related mycoses; such as Candida albicans, Candida glabrata, C. Krusei and Cryptococcus neoformans. In addition, testig will be carried out on at least two Fluconazole-resistant strains of C. albicans. A mechanism-selective assay which detects sterol-dependent antifungal compounds will be used in conjunction with a primary screen using Candida spp. To identify leads with possible novel modes of action. Novel antifungal compounds will be isolated and the structures determined using a variety of spectroscopic techniques and chemical correlations. Activity of new compounds will be compared in vitro with the clinical agents amphotericin B and fluconazole as positive controls to evaluate with in vivo murine models of disseminated mycoses. The strengths of this program include the targeting of emergent pathogenic fungi including Fluconazole-resistant Candida species that are of importance in human health, and maximization of chemical diversity to enhance the chances of discovery of novel antifungal agents.
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