Discovery of 1-Hydroxypyridine-2(1H)-thione-6-carboxylic Acid as a First-in-Class Low-Cytotoxic Nanomolar Metallo β-Lactamase Inhibitor

Woo Shik Shin, Alexander Bergstrom, Robert A. Bonomo, Michael W. Crowder, Ramaiah Muthyala, Yuk Yin Sham

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

VIM-2 is one of the most common carbapenem-hydrolyzing metallo β-lactamases (MBL) found in many drug-resistant Gram-negative bacterial strains. Currently, there is a lack of effective lead compounds with optimal therapeutic potential within our drug development pipeline. Here we report the discovery of 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid (3) as a first-in-class metallo β-lactamase inhibitor (MBLi) with a potent inhibition Ki of 13 nm against VIM-2 that corresponds to a remarkable 0.99 ligand efficiency. We further established that 3 can restore the antibiotic activity of amoxicillin against VIM-2-producing E. coli in a whole cell assay with an EC50 of 110 nm. The potential mode of binding of 3 from molecular modeling provided structural insights that could corroborate the observed changes in the biochemical activities. Finally, 3 possesses a low cytotoxicity (CC50) of 97 μm with a corresponding therapeutic index of 880, making it a promising lead candidate for further optimization in combination antibacterial therapy.

Original languageEnglish (US)
Pages (from-to)845-849
Number of pages5
JournalChemMedChem
Volume12
Issue number11
DOIs
StatePublished - Jun 7 2017

Bibliographical note

Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

  • 1-hydroxypyridine-2(1H)-thiones
  • VIM-2
  • drug resistance
  • metallo β-lactamase
  • pyrithiones
  • β-lactam antibiotics

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