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

Hospital pathogens, including <i>Klebsiella aerogenes</i> 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 <i>de-novo</i> developed, synthesized, and studied the <i>in-vitro</i> and <i>in-silico</i> behavior of four novel broad spectrum antimicrobial peptides, namely PEP01 to PEP04. All four peptides had significant antibacterial action against <i>K. aerogenes.</i> The literature evidence strongly suggests that Beta-lactamases are extremely important for bacteria, including <i>K. aerogenes,</i> 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 <i>K. aerogenes</i>. 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