Probing the interaction mechanisms between three β-lactam antibiotics and penicillin-binding proteins of Escherichia coli by molecular dynamics simulations

The presence of antibiotic residues in the aquatic environments poses great potential risks to the aquatic organisms, and even human health. Elucidating the interaction mechanisms between antibiotics and biomacromolecules is crucial for accurately assessing and preventing their potential risks. Therefore, the toxicity of three beta-lactam antibiotics on Escherichia coli (E. coli) was investigated by using the time-dependent toxicity microplate analysis method in this study. Then, molecular docking and molecular dynamics simulation technologies were used to elucidate the potential molecular interactions between β-lactam antibiotics and penicillin-binding proteins of E. coli, and their correlation with the physical and chemical behaviors observed in the physiological and biochemical experiments. The results show that three antibiotics exert inhibitory effects on E. coli cells by modifying their membrane permeability, and even more severe cell damage including rupture, wrinkling, adhesion, indentation, elongation and size alterations. But, toxic effect of the three antibiotics on E. coli varies, and toxicity order is followed by meropenem > cefoperazone > amoxicillin. Van der Waals forces play a vital role in the molecular interactions between the three antibiotics penicillin binding protein of E. coli and the sequence of binding free energy is consistent with the observed toxicity order. Shape compensation is the principal determinant for the binding of antibiotics to penicillin binding proteins, which pertains to the drug-induced alteration in the three-dimensional conformation of penicillin binding proteins.