Honors College Thesis
 

Identification of Small Molecule Inhibitors of the Staphylococcus aureus Sortase A Enzyme

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  • The Sortase A (SrtA) enzyme is a potential target for a new class of anti-infective drugs because it is responsible for anchoring virulence factors to the surface of pathogenic, Gram-positive bacteria such as Staphylococcus aureus. High throughput screening yielded low molecular weight compounds that inhibit purified SrtA from S. aureus. The efficacy of these compounds at targeting SrtA in live bacteria was successfully determined by developing sensitive biological assays that measure inhibition of sortasedependent surface protein expression in S. aureus. Fibrinogen-clumping and fibrinogenbinding assays were developed to determine the presence of clumping factors (ClfA and B), a fibronectin-binding assay was used to determine the presence of fibrinogen-binding proteins (FnBPA and B), and dot blots were developed to measure protein A on the cell surface. Fifty-six compounds were identified that inhibit surface protein expression in at least one of the biological assays. The effectiveness of these compounds at treating infection will soon be tested in vivo using the S. aureus septic arthritis model in mice.
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