Discovery of 3-aryl substituted benzoxaboroles as broad-spectrum inhibitors of serine- and metallo-β-lactamases

Bioorg Med Chem Lett. 2021 Jun 1:41:127956. doi: 10.1016/j.bmcl.2021.127956. Epub 2021 Mar 17.

Abstract

The production of β-lactamases represents the main cause of resistance to clinically important β-lactam antibiotics. Boron containing compounds have been demonstrated as promising broad-spectrum β-lactamase inhibitors to combat β-lactam resistance. Here we report a series of 3-aryl substituted benzoxaborole derivatives, which manifested broad-spectrum inhibition to representative serine-β-lactamases (SBLs) and metallo-β-lactamases (MBLs). The most potent inhibitor 9f displayed an IC50 value of 86 nM to KPC-2 SBL and micromolar inhibitory activity towards other tested enzymes. Cell-based assays further revealed that 9f was able to significantly reduce the MICs of meropenem in clinically isolated KPC-2-producing bacterial strains and it showed no apparent toxicity in HEK293T cells.

Keywords: Antibiotic resistance; Boron compounds; β-Lactamases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Boron Compounds / chemical synthesis
  • Boron Compounds / chemistry
  • Boron Compounds / pharmacology*
  • Escherichia coli / drug effects
  • Escherichia coli / metabolism
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / metabolism
  • Meropenem / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Protein Conformation
  • beta-Lactamase Inhibitors / chemical synthesis*
  • beta-Lactamase Inhibitors / chemistry
  • beta-Lactamase Inhibitors / pharmacology*

Substances

  • Boron Compounds
  • beta-Lactamase Inhibitors
  • Meropenem