Chemical Biology: Antibiotic Discovery
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The emergence of antibiotic resistance bacteria is significant health concern. Our goal is to discover new anti-infective agents that can be used to combat infections caused by methicillin resistant Staphylococcus aureus (MRSA) and other multidrug resistant Gram-positive bacteria. Toward this objective, we are using high throughput screening approaches to identify small molecules that prevent bacteria from displaying virulence factors. Our research is a collaborative effort with Mike Jung and Hung Ton-That’s research groups at UCLA, and employs computational, structural and synthetic chemistry methods to guide inhibitor optimization. Much of our effort has concentrated on discovering small molecules that inhibit the S. aureus Sortase A (SrtA) enzyme, as they could function as powerful anti-infective agents that work by preventing the display of protein virulence factors. At present, we are exploiting the recently discovered growth dependence of Actinomyces oris on the activity of its SrtA enzyme, which enables the application of powerful cell-based screening methods to identify inhibitors that may have novel molecular scaffolds that are uniquely suited for traversing the cell wall. Our current inhibitor research is also targeting the wall teichoic acid (WTA) biosynthetic pathway, as this highly abundant anionic glycopolymer has critical functions in cell division, morphology, adhesion, and microbial susceptibility to the immune response. The WTA biosynthetic pathway in S. aureus has drawn significant interest as a drug target, as clinically important MRSA strains that lack WTA are defective in host colonization and re-sensitized to beta-lactam antibiotics.
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