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

Abstract

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 (ZINC¹² 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

Keywords:

• New Delhi metallo-β-lactamase 1 (NDM-1)
• inhibitor
• molecular docking
• molecular dynamic simulations
• FDA library
• drug repurposing
• in vitro assays

Acknowledgement

The authors thank Dr. V. Krishnamurthy, DSU for the useful discussions and support to carry out the work, Dr. Anirudha Lakshminarasimhan, Tata Institute of Genetics Society (TIGS), for his expert views and suggestions, Dr. Anshuman Chandra, ICMR-NIMR for extending technical support for virtual screening, Dr. K. M. Kumar from Pondicherry University, for suggestions and Dr. Venkateswarlu Yarlagadda, IIT, Mumbai for his valuable help and suggestions. We are very thankful to Dr. B. R. Shome, ICAR-NIVEDI and Dr. K. L. Ravi Kumar, Dr. Varun Shamanna, Dr. Vandana Govindan, Karnataka Institute of Medical Sciences (KIMS) for giving the bacterial strains with background information.

Conflict of interest

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by seed grants from DSU under project DSU/RC/2020-21ISM/A01 to Susweta Das.