Identification of a novel natural compound inhibitor targeting AmpC β-lactamase to combat multidrug-resistant

Introduction: Antimicrobial resistance (AMR) remains one of the most urgent threats to global public health, driven by the rising prevalence of multidrug-resistant (MDR) pathogens such as Pseudomonas aeruginosa. A key mediator of resistance in this organism is AmpC β-lactamase, an enzyme that confers bacterial survival by hydrolysing β-lactam antibiotics before they can exert their effect. Methods: We screened 374 compounds from the ChemDiv chemical library for novel inhibitors that target this enzyme, with a bias toward natural-compound-derived scaffolds as an alternative to existing resistance-countering strategies. Pharmacokinetic profiling was performed using SwissADME. Molecular dynamics (MD) simulations were carried out to further characterize the stability of the protein-ligand complex. Additionally, free energy perturbation (FEP) calculations were performed to quantitatively verify the binding affinity towards AmpC β-lactamase. Results: Among the screened compounds, compound N094-0017 emerged as the top candidate. It showed good affinity for the AmpC active site and formed stable hydrogen bonds, with a binding energy of -5.6 kcal/mol. SwissADME-based pharmacokinetic profiling suggested desirable drug-like and favourable oral bioavailability profiles. MD simulations were conducted to further characterize the stability of the protein-ligand complex, and the RMSD, RMSF, and SASA profiles were consistent, confirming stable retention of the ligand within the active site throughout the simulation period. Moreover, FEP calculations showed a binding free energy of ∼40 kJ/mol for N094-0017 toward AmpC β-lactamase. Discussion: In conclusion, these data suggest N094-0017 as a promising candidate for an AmpC β-lactamase inhibitor, and natural compounds present a promising strategy for addressing the growing challenge of AMR.