Discovery of Natural Products and Natural Product-Like Inhibitors

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Natural products - small molecules biosynthesized primarily by microorganisms, fungi and invertebrates - are engendered with diverse chemical structures that give rise to a broad range of biological activities. As such, natural products or their synthetic derivatives account for the majority of currently used therapeutics, especially among antibiotics and antitumor agents. With an emphasis on marine invertebrates, we have identified during the last funding period several classes of novel marine natural products that potently inhibit growth of wild type and drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Whole cell and in vitro assays have led to the hypothesis that one class of antibiotics exerts its antibacterial activity through unidentified interactions with the bacterial cell division machinery. Targeting bacterial cell division for the discovery of new antibiotics has recently been validated. Ongoing studies in our laboratory include identification of the target/s of these novel antibiotics through an interdisciplinary approach involving chemical synthesis and whole cell localization and mechanistic studies.