Antifungal sphingolipids for AIDS-related Mycoses

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DESCRIPTION (provided by applicant): Russia has one of the highest rates of increase in new cases of AIDS in the developed world correlated with tumultuous social and economic upheaval in the past decade. The development of novel antifungal drugs with activity against AIDS-related opportunistic fungal disease, joined with regional efforts in drug discovery, is needed. Dimeric sphingolipids, which occur in marine sponges of restricted distribution, exhibit significant synergism in antifungal assays (in vitro) and may be useful leads in development of novel antimycotics with unique or complementary modes of action to clinical drugs. This AIDS-FIRCA proposal seeks to isolate and characterize novel dimeric sphingolipids from marine sponges of the family Leucettidae. New compounds will be isolated using solvent fractionation and chromatography and characterized using a variety of spectroscopic techniques, in particular mass spectrometry nuclear magnetic resonance spectroscopy (NMR) and circular dichroism (CD). Biological activity of pure antifungal compounds will be characterized using in vitro antifungal susceptibility testing in panel of fluconazole-resistant fungi. Lead compounds will be selected for advanced in vivo evaluation in murine models of fungemia.