In silico identification of phytochemical inhibitors against the S1 dihydrofolate reductase variant of Staphylococcus aureus: Overcoming trimethoprim resistance

Abstract

This study addresses the critical challenge of trimethoprim (TMP) resistance in Staphylococcus aureus mediated by the plasmid encoded S1 DHFR variant. Using protein crystal structure (PDB ID: 2W9S), in silico molecular docking was performed to identify phytochemical inhibitors capable of overcoming the structural barriers of the S1 variant, such as a widened active site and M20 loop displacement. A library of phytochemicals from the Jahangirnagar University campus flora was screened against the mutant enzyme. Virtual screening results identified Rutin (−9.5 kcal/mol), Neferine (−9.2 kcal/mol), and Rosmarinic acid (−8.95 kcal/mol) as top candidates with better binding affinities than the standard Trimethoprim (−7.8 kcal/mol). These compounds demonstrate high binding affinity and stability, suggesting their potential to bridge the altered active site of the S1 variant. These early findings provide a molecular docking approach for potentially developing next-generation "resistance-breaking" antibiotics to combat multidrug-resistant methicillin-resistant staphylococcus aureus (MRSA).