Establishing a parallel compound screening method and identifying novel antimicrobial compounds targeting Staphylococcus aureus dihydrofolate reductase

Abstract

The emergence of drug-resistant Staphylococcus aureus strains, such as methicillin-resistant S. aureus and vancomycinresistant S. aureus, and their spread not only inside hospitals but also outside hospitals has become a major problem worldwide. In this study, we investigated novel antimicrobial compounds targeting trimethoprim-resistant S. aureus dihydrofolate reductase (TMP-resistant saDHFR). A novel screening method, called the parallel compound screening (PCS) method, was established to analyze a common population of compounds that showed top scores using two docking tools, GOLD and AutoDock Vina. Using 154,118 compounds in the structural library, we conducted a threestep in silico structure-based drug screening, including PCS, and identified nine candidate compounds targeting TMP-resistant saDHFR. The growth inhibitory effects of the candidate compounds on bacteria were examined on Staphylococcus epidermidis, a model microbial strain of S. aureus. Among the candidate compounds, two compounds showed strong growth inhibition against S. epidermidis. The IC 50 values of the two compounds (6.34 and 56.94 µM) were determined. Molecular dynamics simulations predicted the direct and stable interactions between the active compounds and TMP-resistant saDHFR. The data regarding these active compounds from this study are expected to contribute to the development of new antibacterial agents against drug-resistant strains of S. aureus.