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Superbugs producing New Delhi metallo-β-lactamase 1 (NDM-1) enzyme is a growing crisis, that is adversely affecting the global health care system. NDM-1 empowers the bacteria to inactivate entire arsenal of β-lactam antibiotics including carbapenem (the last resort antibiotic) and remains ineffective to all the available β lactamase inhibitors used in the clinics. Limited therapeutic option available for rapidly disseminating NDM-1 producing bacteria makes it imperative to identify a potential inhibitor for NDM-1 enzyme. With drug repurposing approach, in this study, we used virtual screening of available Food and Drug Administration (FDA) approved chemical library (ZINC 12  database) and captured ‘adapalene’ (FDA drug) as a potent inhibitor candidate for NDM-1 enzyme. Active site docking with NDM-1, showed adapalene with binding energy −9.21 kcal/mol and interacting with key amino acid residues (Asp124, His122, His189, His250, Cys208) in the active site of NDM-1. Further, molecular dynamic simulation of NDM-1 docked with the adapalene at 100 ns displayed a stable conformation dynamic, with relative RMSD and RMSF in the acceptable range. Subsequently,  in vitro  enzyme assays using recombinant NDM-1 protein demonstrated inhibition of NDM-1 by adapalene. Further, the combination of adapalene plus meropenem (carbapenem antibiotic) showed synergistic effect against the NDM-1 producing carbapenem (meropenem) resistant clinical isolates ( Escherichia coli  and  Klebsiella pneumoniae ). Overall, our data indicated that adapalene can be a potential inhibitor candidate for NDM-1 enzyme that can contribute to the development of a suitable adjuvant to save the activity of carbapenem antibiotic against infections caused by NDM-1 positive gram-negative bacteria. Communicated by Ramaswamy H. Sarma

journal of biomolecular structure and dynamics

Identification of a potential inhibitor for New Delhi metallo-β-lactamase 1 (NDM-1) from FDA approved chemical library- a drug repurposing approach to combat carbapenem resistance