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

ChemMedChem. 2017 Jun 7;12(11):845-849. doi: 10.1002/cmdc.201700182. Epub 2017 May 22.


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.

Keywords: 1-hydroxypyridine-2(1H)-thiones; VIM-2; drug resistance; metallo β-lactamase; pyrithiones; β-lactam antibiotics.

MeSH terms

  • Cell Survival / drug effects
  • Escherichia coli / drug effects
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Picolinic Acids / chemical synthesis*
  • Picolinic Acids / pharmacology*
  • Picolinic Acids / toxicity
  • Pseudomonas aeruginosa / drug effects
  • Thiones / chemical synthesis*
  • Thiones / pharmacology*
  • Thiones / toxicity
  • beta-Lactamase Inhibitors / chemistry*
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactamase Inhibitors / toxicity
  • beta-Lactamases / metabolism


  • 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid
  • Picolinic Acids
  • Thiones
  • beta-Lactamase Inhibitors
  • beta-Lactamases