Targeting Peptidoglycan Biosynthesis in Methicillin-Resistant Staphylococcus aureus

Antimicrobial resistance (AMR) has emerged as a critical global health issue, with Methicillin-resistant Staphylococcus aureus (MRSA) being a major contributor. Listed as a “superbug” by the World Health Organization (WHO), MRSA exhibits resistance to β-lactam antibiotics and continues to pose a serious clinical challenge. MurG catalyzes a crucial upstream step in Lipid II biosynthesis, whereas the mecA gene producing PBP2a, which operates at the transpeptidation stage of peptidoglycan production, is the primary mediator of β-lactam resistance in MRSA. MurG inhibition limits substrate availability for PBPs, particularly PBP2a, by interfering with precursor synthesis. Therefore, rather than directly overcoming mecA-mediated resistance, targeting MurG is a mechanistically different approach. This study aimed to discover potential inhibitors of MurG to disrupt MRSA's cell wall formation. Using the STRING database, we confirmed the role of MurG in cell wall biosynthesis and selected it as a therapeutic target. A virtual screening pipeline, including High-Throughput Screening, Standard Precision, and Extra Precision docking, assessed 6.4 million compounds from databases like DrugBank and SelleckChem. The top hits from this screening, STK541784 and STK700190, were further evaluated using ADME/T analysis and molecular dynamic (MD) simulations to determine their binding stability. Docking scores of -6.9 and -9.6, respectively, were achieved for STK541784 and STK700190. The MM/GBSA results showed that STK541784 (-93.94 kcal/mol) and STK700190 (-88.51 kcal/mol) displayed significantly higher binding affinities than standard antibiotics such as Vancomycin (-64.04 kcal/mol) (a clinically used anti-MRSA antibiotic) and Murgocil (-59.86 kcal/mol). Both compounds demonstrated stable interactions in MD simulations. Additionally, KDeep binding affinity calculations revealed -10.6186 kcal/mol for STK541784 and -13.0777 kcal/mol for STK700190, confirming their superior stability and affinity compared to existing treatments. These compounds present promising candidates for further investigation as MurG inhibitors.