Antiinfective therapy with a small molecule inhibitor ofStaphylococcus aureussortase

Significance Antiinfectives, drugs that inhibit virulence strategies of microbial pathogens without affecting bacterial growth, may prevent hospital-acquired infections caused by antibiotic-resistant Staphylococcus aureus . We used virtual screening and synthetic optimization to identify 3,6-disubstituted triazolothiadiazole compounds as inhibitors of sortase, an enzyme that incorporates surface proteins into the staphylococcal envelope. Other Gram-positive bacteria also use sortase for protein assembly in the envelope and disease pathogenesis, suggesting that sortase inhibitors could protect high-risk patients against infection with many nosocomial pathogens.