Abstract:
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.
