Restoring Meropenem Activity Against VIM-1-Producing Klebsiella pneumoniae Through Zinc-Binding Ligands

The growing prevalence of metallo-β-lactamase (MBL)-producing bacteria threatens the clinical efficacy of carbapenems such as meropenem. To investigate potential strategies for restoring β-lactam activity, a panel of compounds was evaluated as putative MBL inhibitors and antibiotic adjuvants. The panel included FDA-approved drugs (carbonic anhydrase inhibitors, an antiviral agent, and a metal chelator), and two novel histidine-pyridine derivatives (D- and L-2-amino-3-(1H-imidazol-4-yl)-N-[2-(pyridin-2-yl)ethyl]propenamides). The latter were synthesized and characterized by NMR spectroscopy and mass spectrometry. Combination assays against Verona Integron-encoded Metallo-β-Lactamase 1 (VIM-1)-producing Klebsiella pneumoniae showed that D-penicillamine and chlorpropamide restored meropenem activity. These effects were supported by time-dependent inhibition and checkerboard assays. Molecular docking and MD simulations with the VIM-1 enzyme further elucidated the putative binding modes of these inhibitors. These results suggest that repurposing the conventional D-penicillamine and chlorpropamide drugs can effectively counteract MBL-mediated resistance.