Disarming superbugs: New frontiers in inhibiting NDM-1 and other clinically relevant metallo-β-lactamases

Abstract

The emergence and global spread of Metallo-β-lactamases (MBLs), particularly New Delhi Metallo-β-lactamase (NDM), Verona Integron-encoded Metallo-β-lactamase (VIM), and Imipenemase (IMP), pose a significant threat to the efficacy of β-lactam antibiotics, including carbapenems, often regarded as the last line of defence against multidrug-resistant bacterial infections. This review comprehensively analyzes recent advances in the development of MBL inhibitors (MBLIs), targeting NDM, VIM, and IMP enzymes with a special focus on NDM-1. The inhibitors are categorized based on key functional groups responsible for their activity, offering insight into the structure activity relationships (SAR) that govern their potency and selectivity. We highlight representative compounds with potent inhibition data (IC₅₀/K_i values), supported by molecular docking studies and where available co-crystal structures with target MBLs to elucidate their binding interactions. Synthetic approaches for these inhibitors are also discussed. This review aims to provide a detailed, functionally organized framework for ongoing efforts in designing potent, broad-spectrum MBL inhibitors capable of restoring the utility of β-lactam antibiotics.