Structural and mechanistic insights into zinc-binding inhibitors of metallo-β-lactamases: From boronic acids to peptide mimics for combating carbapenem resistance.

The global dissemination of multidrug-resistant Gram-negative pathogens, primarily driven by the hydrolytic activity of metallo-β-lactamases (MBLs) such as the New Delhi metallo-β-lactamase-1 (NDM-1), necessitates the urgent development of effective inhibitors to resensitize these bacteria to β-lactam antibiotics. This review comprehensively summarizes recent crystallographic and enzymological insights into the rational design of MBL inhibitors. We critically evaluate key chemotypes equipped with diverse zinc-binding groups (ZBGs), including boronic acids, thiosemicarbazones, phosphonates, sulfur-based compounds (e.g., captopril analogues and bisthiazolidines), ebselen-derived selenium scaffolds, and peptidomimetics. For each structural class, we dissect the precise coordination geometry within mononuclear and binuclear zinc(II) active sites, structure-activity relationship (SAR) trajectories, and the mechanistic interplay between primary metal chelation and transition-state mimicry in dictating binding affinity and enzyme selectivity. Particular emphasis is placed on scaffolds demonstrating potent nanomolar to submicromolar inhibition across clinically critical MBL subclasses (e.g., NDM-1, VIM, IMP, L1, and CphA), robust synergistic effects when co-administered with carbapenems in vitro, and favorable cytotoxicity profiles against mammalian cell lines. Ultimately, this compilation highlights how integrating primary Lewis acid-base zinc interactions (via dative or semi-covalent bonds) with secondary non-covalent contacts within the adjacent active-site subsites provides a robust pharmacophore blueprint for the future discovery of pan-MBL therapeutics. Among the six chemotypes investigated, no single scaffold to date combines broad coverage of subclasses with validated selectivity for human zinc metalloenzymes. Bridging this gap rather than further increasing potency is identified here as the key remaining challenge in this field.