Discovery of S taphylococcus aureus Sortase A Inhibitors Using Virtual Screening and the Relaxed Complex Scheme

Staphylococcus aureus is the leading cause of hospital‐acquired infections in the U nited S tates. The emergence of multidrug‐resistant strains of S . aureus has created an urgent need for new antibiotics. Staphylococcus aureus uses the sortase A enzyme to display surface virulence factors suggesting that compounds that inhibit its activity will function as potent anti‐infective agents. Here, we report the identification of several inhibitors of sortase A using virtual screening methods that employ the relaxed complex scheme, an advanced computer‐docking methodology that accounts for protein receptor flexibility. Experimental testing validates that several compounds identified in the screen inhibit the activity of sortase A . A lead compound based on the 2‐phenyl‐2,3‐dihydro‐1 H ‐perimidine scaffold is particularly promising, and its binding mechanism was further investigated using molecular dynamics simulations and conducting preliminary structure–activity relationship studies.