In silico Discovery of Novel Antibacterial Compounds against Staphylococcus aureus Targeting Extracellular Domain of Lipoteichoic Acid Synthase, Quantum mechanical quantification, and in vitro experimental validation

Staphylococcus aureus is a major causative agent of serious hospital-acquired infections, including pneumonia and sepsis. The emergence of drug-resistant strains such as methicillin-resistant and vancomycin-resistant S. aureus poses a global threat. Infections caused by these multidrug-resistant bacteria are predicted to become a leading cause of human mortality in the future. However, the development pipeline for new antibiotics is declining, raising concerns about a future shortage of effective treatments. Therefore, the discovery of novel antimicrobial agents, particularly those with new mechanisms of action, is urgently needed. In this study, we aimed to discover novel antimicrobial compounds by targeting Lipoteichoic acid synthase (LtaS). LtaS is a membrane protein essential for the synthesis of lipoteichoic acid (LTA), a key cell wall component in S. aureus . We performed a hierarchical in silico screening of the ChemBridge chemical 3D structure library, which contains about 150 thousand compounds. The screening identified a compound (7195703) as a promising lead candidate. Quantum mechanical calculation of DG using the FMO method yielded a value of -93.64 kcal/mol. To evaluate its antimicrobial activity, an in vitro growth inhibition assay was performed using Staphylococcus epidermidis , a closely related model organism for S. aureus . 7195703 exhibited potent and dose-dependent growth inhibition against S. epidermidis , with a half-maximal inhibitory concentration (IC ₅₀ ) of 16.61 µM. Conversely, 7195703 showed no significant inhibitory activity against the Gram-negative bacterium Escherichia coli , suggesting its selective activity against certain Gram-positive bacteria. Furthermore, a search for structural analogues of 7195703 identified five derivatives that also displayed antimicrobial activity.