In silico Evaluation of Marine Phage Tail Proteins as Inhibitors of β-Lactamases: A Novel Approach to Combat Antibiotic Resistance

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Abstract
Antibiotic resistance poses a significant global health threat, necessitating innovative strategies to combat bacterial infections. β-lactamases, enzymes that hydrolyze β-lactam antibiotics, contribute significantly to antibiotic resistance. Phage therapy, utilizing bacteriophages to target β-lactamases, holds promise as an alternative treatment approach. In this study, we investigated the binding affinities between extended-spectrum β-lactamases (ESBLs), metallo-β-lactamases (MBLs), and AmpC-type β-lactamases with marine phages. Molecular modeling, molecular docking, and molecular dynamics simulations were employed using I-TASSER, AutoDock Vina, and GROMACS software to explore the interactions between tail tube proteins of selected marine phages (P-SSM2, P-SSM4, and P-SM2) and various β-lactamases. Among ESBLs, KPC-2 consistently exhibited the highest binding free energy, indicating robust interactions with marine phages. Similarly, among all MBLs, NDM-1 and VIM-1 showed superior binding free energies across all phage complexes. In addition, among AmpC-type beta-lactamases, CMY-2 displayed higher binding affinities across various phage complexes than DHA-1. In silico analyses suggest that marine phage tail proteins may interact with β-lactamases in a manner that could potentially mitigate antibiotic resistance. The differential binding affinities observed highlight the versatility of marine phages in targeting specific beta-lactamases. This novel approach could lead to the development of novel therapeutic strategies for multidrug-resistant gram-negative infections.

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