Bacterial Metabolite-Derived NDM-1 Inhibitors: A Computational Strategy to Overcome β-Lactam Resistance

The emergence of New Delhi metallo-β-lactamase-1 (NDM-1) poses a major challenge to antibiotic therapy. This study addresses the urgent need for effective NDM-1 inhibitors by investigating bacterial-derived natural metabolites as potential therapeutic agents. A total of 300 bacterial secondary metabolites were screened using an induced-fit docking model, targeting key active site residues essential for NDM-1 enzymatic activity. Among them, 21 metabolites showed stronger binding affinities (- 6.8 to - 5.8 kcal/mol) than the standard drug meropenem and followed drug-likeness criteria. The top six candidates (tumonoic acid H, vitroprocine C, borrelidin, 2-hepta-1,5-dienyl-3,6-dihydroxy-5-(3-methylbut-2-enyl) benzaldehyde (HDB), gageomacrolactin 1, and 4,4'-oxybis (3-phenylpropionic acid)) formed strong interactions with catalytic residues such as His122, Asp124, and His250. These interactions involved Zn2⁺ chelation and binding to the active-site water molecule (H₂O-420), suggesting potential NDM-1 inhibition. Molecular dynamics simulations of the top three complexes (tumonoic acid H, vitroprocine C, and borrelidin) revealed favorable stability, compactness, limited solvent exposure, and coordinated motion. Pharmacophore modeling confirmed critical interaction features. These hits showed favorable safety, bioactivity, and no structural alerts. They also displayed good synthetic feasibility. Overall, this study identifies natural metabolites as promising NDM-1 inhibitors and supports further experimental validation against antibiotic resistance.