Exploring PBP2a resistance in MRSA by comparison between molecular covalent docking and non-covalent docking

Background and objectivesThe presence of penicillin-binding protein 2a (PBP2a) is the cause of Methicillin-resistant Staphylococcus aureus (MRSA), which is important nosocomial pathogens worldwide and now are also of growing importance in community-acquired infection. The PBP2a resistance depends upon a supplementary peptidoglycan transpeptidase, which continues to function when normal PBPs have been inactivated by beta-lactam antibiotics. Analysis and quantitative study of the molecular interactions of PBP2a against {beta}-lactam antibiotics are required, as they support explaining and enhance understanding of the structure-activity relationship of antibiotic resistance. MethodsBioinformatics and computational methods have been highly effective tools for {beta}-lactams targeting PBPs to tackle the urgent threat of antimicrobial resistance. Regarding {beta}-lactam antibiotics targeting PBP2a and PBPs, we applied different docking programs to illustrate inhibition mode, MM/GBSA to estimate the binding free energies, and molecular dynamic simulation to validate and analyze the molecular interactions. ResultsBased on {beta}-lactam antibiotics targeting PBPs as covalent inhibitors, covalent docking was employed to provide explicit models of PBP2a against susceptible {beta}-lactam antibiotics. The simultaneous use of non-covalent docking enhances our comprehensive comprehension of the resistance of PBP 2a, which resulted from the lack of covalent linked to {beta}-lactam antibiotics. The selected antibiotics strongly interact with PBP2a, revealing the essential amino acid residues and binding affinity for inhibition. MD simulations were performed for the ligand-bound state of PBP-2a to explain their interaction and conformational changes. These findings are also strongly supported by root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF) and Hydrogen bond analysis of the protein-ligand complex. ConclusionsOur research offers extensive knowledge of the PBP2a-lactam interactions for the ability of known antibiotics to combat MRSA. The simulation results indicating stability and accuracy provide valuable insights for the advancement of pharmaceutical interventions against infectious diseases O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/639213v1_ufig1.gif" ALT="Figure 1"> View larger version (88K): org.highwire.dtl.DTLVardef@1dc180forg.highwire.dtl.DTLVardef@afb81borg.highwire.dtl.DTLVardef@6014c4org.highwire.dtl.DTLVardef@1f35113_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure abstract:C_FLOATNO The interaction of Methicillin with PBP2a of MRSA. The protein is shown as a cartoon model, and the covalent binding of the ligand and serine active site is shown as a stick model. C_FIG