Discovery of Antibacterial Compounds with Potential Multi-Pharmacology against Staphylococcus Family Members by In Silico Structure-Based Drug Screening.

() is a major bacterial infection in humans, leading to severe disease and causing death. The stagnation of antibiotic development in recent decades has made it difficult to combat drug-resistant infections. In this study, we performed an in silico structure-based drug screening (SBDS) targeting the MurE (saMurE) enzyme involved in cell wall synthesis of S. aureus. saMurE is an enzyme that is essential for the survival of but not present in humans. SBDS identified nine saMurE inhibitor candidates, Compounds -, from a structural library of 154,118 compounds. Among them, Compound showed strong antibacterial activity against () used as a model bacterium. Amino acid sequence homology between saMurE and MurE is 87.4%, suggesting that Compound has a similar inhibitory effect on . Compound showed an IC value of 301 nM for in the dose-dependent growth inhibition assay. Molecular dynamics simulation showed that Compound binds stably to both MurD and MurF, suggesting that it is a potential multi-pharmacological pharmacological inhibitor. The structural and bioactivity information of Compound , as well as its potential multiple-target activity, could contribute to developing new antimicrobial agents based on MurE inhibition.