Combating New Delhi metallo-beta-lactamase-1 (NDM-1): an integrated review of inhibitor development and next-generation therapeutic platforms

Abstract

New Delhi metallo-β-lactamase-1 (NDM-1), which has emerged globally, exhibits resistance to almost all β-lactam antibiotics, including carbapenems, posing a major challenge to modern antibiotic therapy. Deep sequencing has revealed the evolution of several new NDM variants (some of the variants are more thermostable than NDM-1) due to mutations that increase their zinc-binding and catalytic efficiency and establish a selective pressure on the enzymes. In addition to enzymatic breakdown, NDM-mediated resistance is exorbitantly exhibited via porin loss, efflux pump activity, biofilm formation, and outer membrane vesicle-mediated dissemination. Despite the urgent need for effective countermeasures, no clinically approved inhibitor of NDM-1 has been developed. This review explores the structural and functional characteristics of NDM-1, together with the epidemiology of blaNDM-1-harbouring bacterial pathogens. It further elaborates the catalytic basis of the broad-spectrum β-lactam hydrolysis mechanism, attributed to the presence of dinuclear Zn(ii); the conserved αβ/βα metallo-β-lactamase fold, and flexible active-site loops that govern substrate recognition are also highlighted. In addition, this review provides details on the known inhibitor classes, including thiol-based compounds, hydroxamates, bicyclic boronates, repurposed drugs, and natural products, and discusses the challenges related to pharmacokinetics, toxicity, and variant-specific effectiveness. Other emerging approaches, such as CRISPR-Cas systems for targeted gene editing, nanoparticle-based delivery platforms, and artificial intelligence-driven drug discovery, are also explored as promising options for future therapy development.