Characterization of a novel inhibitor for the New Delhi metallo-β-lactamase-4: Implications for drug design and combating bacterial drug resistance

James B. Thoden, Bogdan M. Benin, Adam Priebe, Woo Shik Shin, Ramaiah Muthyala, Yuk Yin Sham, Hazel M. Holden

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The bacterial metallo-β-lactamases (MBLs) catalyze the inactivation of β-lactam antibiotics. Identifying novel pharmacophores remains crucial for the clinical development of additional MBL inhibitors. Previously, 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid, hereafter referred to as 1,2-HPT-6-COOH, was reported as a low cytotoxic nanomolar β-lactamase inhibitor of Verona-integron-encoded metallo-β-lactamase 2, capable of rescuing β-lactam antibiotic activity. In this study, we explore its exact mechanism of inhibition and the extent of its activity through structural characterization of its binding to New Delhi metallo-β-lactamase 4 (NDM-4) and its inhibitory activity against both NDM-1 and NDM-4. Of all the structure-validated MBL inhibitors available, 1,2-HPT-6-COOH is the first discovered compound capable of forming an octahedral coordination sphere with Zn2 of the binuclear metal center. This unexpected mechanism of action provides important insight for the further optimization of 1,2-HPT-6-COOH and the identification of additional pharmacophores for MBL inhibition.

Original languageEnglish (US)
Article number105135
JournalJournal of Biological Chemistry
Volume299
Issue number9
DOIs
StatePublished - Sep 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

  • antibiotic resistance
  • antibiotics
  • computational biology
  • crystallography
  • enzyme kinetics
  • enzyme structure

PubMed: MeSH publication types

  • Journal Article

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