Methicillin-resistant Staphylococcus aureus (MRSA) severely affects human health, including the skin glands, nasal cavity, wound infections, bone infections, and pneumonia. Among the most effective MRSA drugs, Cefoxitin also develops resistance due to mutations in the mecA gene. Four mutations at positions E229K, E239R, G246K, and E447K are classified as high-level resistance mutations. However, the resistance mechanism of MRSA towards Cefoxitin caused by these mutations is still unclear, as there is less information available regarding the structural and functional effects of the mutations against Cefoxitin. Therefore, our present study was designed to explore the mechanisms of binding interactions between wild-type and mutated PBP2a against Cefoxitin using molecular docking and MD simulations. Subsequently, we identified that the mutant form of PBP2a affects the activity of Cefoxitin. Interestingly, the binding of Cefoxitin with G246K and E239R mutants demonstrates unstable behavior compared to E447K-Cefoxitin and E229K-Cefoxitin. In this study, we propose the resistance mechanism of Cefoxitin at the atomic level. The proposed drug-resistance mechanism will provide valuable guidance for the design of MRSA drugs. This research might provide a new framework for designing new agents against the mutated form of PBP2a.Communicated by Ramaswamy H. Sarma.
Keywords: Molecular docking; antibiotic resistance; gene mutation; simulation.