Discovery of Cyclic Boronic Acid QPX7728, an Ultrabroad-Spectrum Inhibitor of Serine and Metallo-β-lactamases

J Med Chem. 2020 Jul 23;63(14):7491-7507. doi: 10.1021/acs.jmedchem.9b01976. Epub 2020 Apr 2.


Despite major advances in the β-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are the class B (metallo) enzyme NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of Acinetobacter baumannii. Continuing the boronic acid program that led to vaborbactam, efforts were directed toward expanding the spectrum to allow treatment of a wider range of organisms. Through key structural modifications of a bicyclic lead, stepwise gains in spectrum of inhibition were achieved, ultimately resulting in QPX7728 (35). This compound displays a remarkably broad spectrum of inhibition, including class B and class D enzymes, and is little affected by porin modifications and efflux. Compound 35 is a promising agent for use in combination with a β-lactam antibiotic for the treatment of a wide range of multidrug resistant Gram-negative bacterial infections, by both intravenous and oral administration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bacteria / drug effects
  • Borinic Acids / chemistry
  • Borinic Acids / pharmacokinetics
  • Borinic Acids / pharmacology*
  • Borinic Acids / therapeutic use
  • Boronic Acids / chemistry
  • Boronic Acids / pharmacokinetics
  • Boronic Acids / pharmacology*
  • Boronic Acids / therapeutic use
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacokinetics
  • Carboxylic Acids / pharmacology*
  • Carboxylic Acids / therapeutic use
  • Drug Discovery
  • Klebsiella Infections / drug therapy
  • Mice
  • Microbial Sensitivity Tests
  • Structure-Activity Relationship
  • beta-Lactamase Inhibitors / chemistry
  • beta-Lactamase Inhibitors / pharmacokinetics
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactamase Inhibitors / therapeutic use


  • Borinic Acids
  • Boronic Acids
  • Carboxylic Acids
  • QPX7728
  • beta-Lactamase Inhibitors