The Discovery of Novel Agents against Staphylococcus aureus by Targeting Sortase A: A Combination of Virtual Screening and Experimental Validation.

Staphylococcus aureus (S. aureus) , commonly known as "superbugs", is a highly pathogenic bacterium that poses a serious threat to human health. There is an urgent need to replace traditional antibiotics with novel drugs to combat S. aureus . Sortase A (SrtA) is a crucial transpeptidase involved in the adhesion process of S. aureus . The reduction in virulence and prevention of S. aureus infections have made it a significant target for antimicrobial drugs. In this study, we combined virtual screening with experimental validation to identify potential drug candidates from a drug library. Three hits, referred to as Naldemedine, Telmisartan, and Azilsartan, were identified based on docking binding energy and the ratio of occupied functional sites of SrtA. The stability analysis manifests that Naldemedine and Telmisartan have a higher binding affinity to the hydrophobic pockets. Specifically, Telmisartan forms stable hydrogen bonds with SrtA, resulting in the highest binding energy. Our experiments prove that the efficiency of adhesion and invasion by S. aureus can be decreased without significantly affecting bacterial growth. Our work identifies Telmisartan as the most promising candidate for inhibiting SrtA, which can help combat S. aureus infection.