Exploring PBP2a resistance in MRSA by comparison between molecular covalent docking and non-covalent docking
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Background and objectives
The 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 β-lactam antibiotics are required, as they support explaining and enhance understanding of the structure-activity relationship of antibiotic resistance.
Methods
Bioinformatics and computational methods have been highly effective tools for β-lactams targeting PBPs to tackle the urgent threat of antimicrobial resistance. Regarding β-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.
Results
Based on β-lactam antibiotics targeting PBPs as covalent inhibitors, covalent docking was employed to provide explicit models of PBP2a against susceptible β-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 β-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.
Conclusions
Our 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
Abstract Figure
Figure abstract: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.
