Rational design of 1H-pyrrole-2-carboxylic acid inhibitors of NDM-1 metallo-β-lactamase restoring β-lactam efficacy against resistant Enterobacterales

Antimicrobial resistance mediated by metallo-β-lactamases (MBLs) represents a critical challenge for the efficacy of β-lactam Antibiotics. Here, we report the design, synthesis, and evaluation of a novel class of 3,5-diaryl-1H-pyrrole-2-carboxylic acids as potent New Delhi Metallo-β-lactamase (NDM)-type MBL inhibitors. Guided by molecular modeling and structure-activity relationship studies, the pyrrole scaffold was optimized through systematic modifications of the phenyl rings at position 3 and 5 of pyrrole core, yielding derivatives with low-nanomolar IC₅₀ values against NDM-1. Key interactions involve coordination of the pyrrole carboxyl groups with Zn²⁺ ions and hydrogen bonding with active-site residues, supporting enhanced binding and inhibitory potency. Lead compounds restored the activity of cefepime and meropenem against NDM-positive E. coli and K. pneumoniae strains, while triple combinations with serine β-lactamase inhibitors further enhanced antimicrobial efficacy. These results highlight 1H-pyrrole-2-carboxylic acids as a versatile scaffold for MBL inhibition and provide a rational framework for the development of therapeutics against multidrug-resistant pathogens.