B.S. in Biology and Chemistry, 2004,
Research at TSRI:
One potential “lost antibiotic” is Arylomycin A2, a bacterial Signal Peptidase inhibitor that displays activity against a few obscure soil bacteria but is ineffective against almost all human pathogens. By studying the evolution of resistance in the few species of bacterial that are Arylomycin A2 sensitive, I have discovered a critical and previously unappreciated allele within Signal Peptidase that confers high level resistance to this antibiotic. Using genetics, biochemistry, and phylogenetics, I am studying the mechanism by which this allele confers resistance and how widespread this mechanism is in nature. My studies indicate that Arylomycin A2 was once a broad spectrum agent and imposed a significant selective pressure in the evolution of the Signal Peptidase binding pocket. Furthermore, knowledge of how resistance to Arylomycin A2 emerged in nature suggests modifications that could restore this broad spectrum activity. More importantly, if these results are generalizable, they suggest that discovery and re-engineering of “lost antibiotics” could provide the foundation for future generations of antimicrobial therapies. Investigations as to the generality of this model are currently underway.
“SOS Regulatory Elements are Essential for UPEC Pathogenesis” Li B., Smith P., Horvath D, Romesberg F., Justice S. (manuscript in preparation)
“Combating bacteria and drug resistance by inhibiting mechanisms of persistence and adaptation” Smith P., Romesberg F. Nat. Chem. Bio., 2007, 3, 549-556.
“Structural and Initial Biological Analysis of Synthetic Arylomycin A2” Roberts T., Smith P., Cirz R., Romesberg F. J. Am. Chem. Soc., 2007, 129, 15830-15838.
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