Marine Fatty Acids as New Antifungal, Antimycobacterial, and Topo-l Agents

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DESCRIPTION (provided by applicant): Fatty acids play a critical role in human health. Our research group has been active in discovering new fatty acids from marine biota whose structures differ significantly from those of fatty acids normally encountered in terrestrial organisms. It is our aim to study further these novel fatty acids so as to better understand their biochemistry and their potential use in health related problems. In particular, we wish to answer the following questions: 1) Are the structural features of the novel marine fatty acids sufficiently different from those present in common fatty acids so as to significantly alter their biogenesis in prokaryotic and eukaryotic cells? 2) Will the marine fatty acids be sufficiently different from the more common and better studied fatty acids in their toxicity towards pathogenic agents such as fungi and/or mycobacteria? 3) Will the marine fatty acids be useful in helping to prevent and/or control diseases arising from fungi and mycobacteria? If the most unusual marine fatty acids are toxic to the causative agents of infectious diseases, then we can use them in food formulations and supplements that could help in the prevention, reduction, and/or treatment of fungal infections and/or more complex diseases such as tuberculosis. Our long-range goal, therefore, is to identify novel marine fatty acids with the potential of helping in the prevention, reduction, and/or treatment of infectious diseases. The objective of this application, which is the next step toward attainment of our long-range goal, is to explore the chemistry and toxicity of 2-methoxylated 5,9-diunsaturated fatty acids, mid-chain methoxylated fatty acids, and 4,5-methylene fatty acids by: (1) developing the first synthesis for racemic and quiral 2-methoxylated 5,9-diunsaturated fatty acids and determining their antimycobacterial, InhA, and topoisomerase-l inhibitory activities, (2) synthesizing a series of mid-chain methoxylated fatty acids and study their enoyl reductase (EcFabl) inhibitory activity, (3) developing the first synthesis for racemic and optically active 4,5-methylene fatty acids and determining their antifungal and antimycobacterial potential, and (4) carrying out a developmental plan to achieve competitiveness of the PI for non-SCORE support. At the end of this project we will provide new fatty acids that will be made available to biochemists, cell biologists, and pharmacologists to be used against these diseases. The novel antifungal compounds could also be used as yeast and mold inhibitors in food stuffs and as systematic antifungals.