Probing intermolecular interactions and binding stability of antimicrobial peptides with beta-lactamase of Klebsiella aerogenes by comparing FDA approved beta-lactam drugs: a docking and molecular dynamics approach

Hospital pathogens, including Klebsiella aerogenes are becoming increasingly common, with the rise of Beta-lactam-resistant strains, especially in isolates recovered from intensive care rooms. Beta-lactamases participate in both the antibacterial activity and the mediation of the antibiotic resistance of Beta-lactams. The rapid spread of broad-spectrum Beta-lactam antibiotic resistance in pathogenic bacteria has recently become a major global health problem. As a result, new drugs that specifically target Beta-lactamases are urgently needed, and this enzyme has been identified to resolve the problem of bacterial resistance. In previous work, we de-novo developed, synthesized, and studied the in-vitro and in-silico behavior of four novel broad spectrum antimicrobial peptides, namely PEP01 to PEP04. All four peptides had significant antibacterial action against K. aerogenes. The literature evidence strongly suggests that Beta-lactamases are extremely important for bacteria, including K. aerogenes, and hence are therapeutically important and possible targets. Therefore, in this study we incorporated molecular modeling, docking, and simulation studies of the above four AMPs against the Beta-lactamase protein of K. aerogenes. The docking findings were also compared to eight FDA approved Beta-lactam antibiotics. According to our findings, all four peptides have strong binding affinity and interactions with Beta-lactamases and PEP02 has the highest docking score. In MD simulations, the protein-peptide complexes were more stable at 50 ns. We found that the new AMP-PEP02 is the most efficient and suitable drug candidate for inactivating Beta-lactamase protein, and that it is an alternative to or complements existing antibiotics for managing Beta-lactamase related resistance mechanisms based on this computational conclusion.Communicated by Ramaswamy H. Sarma.