Boronic acid inhibitors of the class A β-lactamase KPC-2

Bioorg Med Chem. 2018 Jul 15;26(11):2921-2927. doi: 10.1016/j.bmc.2018.04.055. Epub 2018 Apr 27.

Abstract

The rapid rise of antimicrobial resistance is one of the greatest challenges currently facing medical science. The most common cause of resistance to β-lactam antibiotics is the expression of β-lactamase enzymes, such as KPC-2. As such the development of novel inhibitors of KPC-2 and related enzymes is of the upmost importance. We report the design and synthesis of novel boronic acid transition state analogs containing a 1,4-substituted 1,2,3-triazole linker based on the known inhibitor 3-nitrophenyl boronic acid and demonstrate that they are promising scaffolds for the development inhibitors of KPC-2 with the ability to recover sensitivity to the antibiotic cefotaxime.

Keywords: Antibiotic resistance; Beta-lactamase; Boronic acid inhibitors; KPC.

MeSH terms

  • Boronic Acids / chemistry*
  • Boronic Acids / pharmacology
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / drug effects
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Molecular Structure
  • beta-Lactamases / drug effects*

Substances

  • Boronic Acids
  • Enzyme Inhibitors
  • beta-lactamase KPC-2
  • beta-Lactamases