Ligand-Based Drug Design of Novel Antimicrobials against Staphylococcus aureus by Targeting Bacterial Transcription.

Staphylococcus aureus is a common human commensal pathogen that causes a wide range of infectious diseases. Due to the generation of antimicrobial resistance, the pathogen becomes resistant to more and more antibiotics, resulting in methicillin-resistant S. aureus (MRSA) and even multidrug-resistant S. aureus (MDRSA), namely 'superbugs'. This situation highlights the urgent need for novel antimicrobials. Bacterial transcription, which is responsible for bacterial RNA synthesis, is a valid but underutilized target for developing antimicrobials. Previously, we reported a novel class of antimicrobials, coined nusbiarylins, that inhibited bacterial transcription by interrupting the protein-protein interaction (PPI) between two transcription factors NusB and NusE. In this work, we developed a ligand-based workflow based on the chemical structures of nusbiarylins and their activity against S. aureus . The ligand-based models-including the pharmacophore model, 3D QSAR, AutoQSAR, and ADME/T calculation-were integrated and used in the following virtual screening of the ChemDiv PPI database. As a result, four compounds, including J098-0498 , 1067-0401 , M013-0558 , and F186-026 , were identified as potential antimicrobials against S. aureus , with predicted pMIC values ranging from 3.8 to 4.2. The docking study showed that these molecules bound to NusB tightly with the binding free energy ranging from -58 to -66 kcal/mol.