Novel Inhibitors Targeting Class B1 Metallo-β-Lactamases in Carbapenem-Resistant Acinetobacter baumannii

The rise of multidrug resistance (MDR) in Acinetobacter baumannii has severely compromised the efficacy of carbapenem antibiotics. This resistance is primarily driven by class B1 metallo-β-lactamases (MBLs), including IMP, VIM, and NDM, which hydrolyze a broad spectrum of β-lactams, including carbapenems. To address this challenge, we conducted an extensive structure-based virtual screening campaign specifically targeting IMP-2, VIM-1, and NDM-1, integrating high-throughput docking, ADME/T filtering, and molecular dynamics validation to identify novel inhibitors. In total, 66,734 compounds from the ENAMINE, CMNPD, ASINEX, and ChemDiv libraries were evaluated, with marine-derived CMNPD molecules showing superior drug-likeness and binding potential. Virtual screening was performed using the Schrödinger suite, and top-ranked hits were validated using GROMACS-based molecular dynamics simulations, MM-GBSA binding free energy calculations, and essential dynamics analysis to confirm stability and binding efficiency. Three lead inhibitors, CMNPD29415 (IMP-2; XP G-score: -14.17 kcal/mol; MM-GBSA: -84.53 kcal/mol), CMNPD8077 (VIM-1; -11.76 kcal/mol; MM-GBSA: -50.11 kcal/mol), and BDE_30700625 (NDM-1; -13.80 kcal/mol), exhibited stable protein-ligand interactions and robust dynamic behavior. Key interactions were observed with catalytic residues, including GLU24, HIS35, GLU153, ASP224, and HIS240, supporting their inhibitory potential. MD trajectories revealed low RMSD fluctuations and reduced active-site mobility, further strengthening the therapeutic relevance of these compounds. Overall, this study highlights structurally unique marine metabolites as promising inhibitory scaffolds against Class B1 MBLs, and upcoming experimental validation will determine their translational applicability.