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

<i>Staphylococcus aureus</i> (<i>S. aureus</i>) 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 <i>S. aureus</i> MurE (saMurE) enzyme involved in cell wall synthesis of S. aureus. saMurE is an enzyme that is essential for the survival of <i>S. aureus</i> but not present in humans. SBDS identified nine saMurE inhibitor candidates, Compounds <b>1</b>-<b>9</b>, from a structural library of 154,118 compounds. Among them, Compound <b>2</b> showed strong antibacterial activity against <i>Staphylococcus epidermidis</i> (<i>S. epidermidis</i>) used as a model bacterium. Amino acid sequence homology between saMurE and <i>S. epidermidis</i> MurE is 87.4%, suggesting that Compound <b>2</b> has a similar inhibitory effect on <i>S. aureus</i>. Compound <b>2</b> showed an IC₅₀ value of 301 nM for <i>S. epidermidis</i> in the dose-dependent growth inhibition assay. Molecular dynamics simulation showed that Compound <b>2</b> binds stably to both <i>S. aureus</i> MurD and <i>S. aureus</i> MurF, suggesting that it is a potential multi-pharmacological pharmacological inhibitor. The structural and bioactivity information of Compound <b>2</b>, as well as its potential multiple-target activity, could contribute to developing new antimicrobial agents based on MurE inhibition.