Synergistic Potential of Repurposing non-β-lactam Compounds as Class A serine β-lactamases Inhibitor: Insights from MolecularDocking, Molecular Dynamics Simulations and Antimicrobial Potentiation

Abstract

The global dissemination of extended-spectrum β-lactamases (ESBLs) represents an urgent public health challenge. This study employed a drug repurposing strategy integrating in-silico screening, molecular dynamics (MD) simulations, and in-vitro validation to identify FDA-approved compounds capable of potentiating β-lactam antibiotics against ESBL-producing bacteria. Structure-based virtual screening of 400 FDA-approved compounds against SHV-1 β-lactamase (PDB: 4ZAM) identified 28 compounds with promising binding energies. Four commercially available compounds; epinephrine, omeprazole, sulfadimethoxine, and captopril exhibited binding energies ranging from − 8.15 to − 9.58 kcal/mol with RMSD values of 1.5–2.3 Å, comparable to the reference inhibitor avibactam. MD simulations (250 ns) confirmed the stability of all protein–ligand complexes, with the SHV-1/epinephrine complex demonstrating the lowest RMSD (0.155 nm) and most compact structure. In-vitro evaluation against an ESBL-producing Escherichia coli clinical isolate revealed that epinephrine and omeprazole effectively enhanced antibiotic activity in disk diffusion assays. The ceftriaxone/omeprazole combination achieved the highest potentiation (20 mm at 250 µg/mL), followed by ceftriaxone/epinephrine (18 mm at 250 µg/mL) and cefuroxime/omeprazole (19 mm at 125 µg/mL). Notably, captopril showed no in-vitro activity despite favorable computational predictions, underscoring the importance of experimental validation in drug discovery. These findings highlight the potential of epinephrine and omeprazole as readily available adjuvants against Class A serine β-lactamases, offering a cost-effective strategy to combat ESBL-mediated antibiotic resistance.