Pharmacological Inhibition and Plasmid Curing as Dual Trajectories for Reversal of New Delhi Metallo β Lactamase: A Systematic Review of Experimental and Translational Strategies

Abstract

Antimicrobial resistance driven by New Delhi metallo β lactamase represents a formidable global health crisis, eroding the efficacy of carbapenems and threatening the treatment of severe Gram negative infections. This systematic review synthesises ten pivotal investigations published between 2010 and 2025 that collectively address two principal reversal strategies: pharmacological inhibition of NDM enzymes and genetic destabilisation of bla_NDM plasmids. Literature retrieval across PubMed, Scopus, Web of Science and ScienceDirect yielded 832 records, of which 10 met the inclusion criteria after rigorous screening.

Pharmacological interventions were dominated by rationally designed scaffolds such as thiosemicarbazones and dipyridyl derivatives, which demonstrated nanomolar to submicromolar inhibition with restoration of carbapenem activity in resistant isolates. Repurposing of FDA approved molecules, including dexrazoxane, provided immediate translational value and yielded survival benefits in murine sepsis models, although potency remained modest compared with novel ligands. Natural products and peptide based inhibitors expanded the mechanistic spectrum by introducing allosteric and non zinc dependent modalities, underscoring chemical diversity in inhibitory design.

Plasmid focused studies revealed the genetic complexity of bla_NDM carriage, highlighting addiction systems, conjugation modules, and incompatibility backbones that complicate curing strategies. Nonetheless, genomic insights and proof of concept approaches suggest that CRISPR based nucleases or engineered incompatibility plasmids may provide future solutions for permanent elimination.

The evidence collectively indicates that pharmacological adjuvants and plasmid curing approaches are conceptually complementary. A combined trajectory, integrating immediate translational candidates with long term genetic extirpation, offers the most coherent pathway toward reversing the clinical impact of NDM mediated resistance.