4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors

Bioorg Chem. 2021 Aug:113:105024. doi: 10.1016/j.bioorg.2021.105024. Epub 2021 May 26.

Abstract

In Gram-negative bacteria, the major mechanism of resistance to β-lactam antibiotics is the production of one or several β-lactamases (BLs), including the highly worrying carbapenemases. Whereas inhibitors of these enzymes were recently marketed, they only target serine-carbapenemases (e.g. KPC-type), and no clinically useful inhibitor is available yet to neutralize the class of metallo-β-lactamases (MBLs). We are developing compounds based on the 1,2,4-triazole-3-thione scaffold, which binds to the di-zinc catalytic site of MBLs in an original fashion, and we previously reported its promising potential to yield broad-spectrum inhibitors. However, up to now only moderate antibiotic potentiation could be observed in microbiological assays and further exploration was needed to improve outer membrane penetration. Here, we synthesized and characterized a series of compounds possessing a diversely functionalized alkyl chain at the 4-position of the heterocycle. We found that the presence of a carboxylic group at the extremity of an alkyl chain yielded potent inhibitors of VIM-type enzymes with Ki values in the μM to sub-μM range, and that this alkyl chain had to be longer or equal to a propyl chain. This result confirmed the importance of a carboxylic function on the 4-substituent of 1,2,4-triazole-3-thione heterocycle. As observed in previous series, active compounds also preferentially contained phenyl, 2-hydroxy-5-methoxyphenyl, naphth-2-yl or m-biphenyl at position 5. However, none efficiently inhibited NDM-1 or IMP-1. Microbiological study on VIM-2-producing E. coli strains and on VIM-1/VIM-4-producing multidrug-resistant K. pneumoniae clinical isolates gave promising results, suggesting that the 1,2,4-triazole-3-thione scaffold worth continuing exploration to further improve penetration. Finally, docking experiments were performed to study the binding mode of alkanoic analogues in the active site of VIM-2.

Keywords: 1,2,4-triazole-3-thione; Bacterial resistance; Metallo-β-Lactamase; β-lactam antibiotic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology
  • Binding Sites
  • Cell Survival / drug effects
  • Drug Resistance, Multiple, Bacterial / drug effects
  • Escherichia coli / enzymology
  • HeLa Cells
  • Humans
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / isolation & purification
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Protein Binding
  • Structure-Activity Relationship
  • Thiones / chemistry*
  • Thiones / metabolism
  • Triazoles / chemistry
  • beta-Lactamase Inhibitors / chemistry*
  • beta-Lactamase Inhibitors / metabolism
  • beta-Lactamases / chemistry*
  • beta-Lactamases / metabolism

Substances

  • Anti-Bacterial Agents
  • Thiones
  • Triazoles
  • beta-Lactamase Inhibitors
  • 1,2,4-triazole
  • beta-lactamase bla(vim-2)
  • beta-Lactamases