Discovery of Natural Products and Natural Product-Like Inhibitors

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Natural products, collectively known as small molecules that are biosynthesized 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 therapeutics currently in clinical use, especially among the antibiotic and antitumor drug classes. With the growing incidence of bacterial infections, many of which are caused by bacteria that are unaffected by standard antibiotic treatments (so-called drug-resistant bacteria), there is a particular need for basic and clinical research aimed at the discovery and development of new classes of antibiotics. With an emphasis on marine invertebrates as natural product source organisms, we have identified 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 our recently reported antibiotics exerts its antibacterial activity through interactions with the bacterial cell division machinery, a validated target for antibiotic discovery. 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. A long-term goal of this research includes identification of tractable lead compounds that can be used to treat bacterial infections caused by antibiotic-resistant bacteria.