Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases

J Med Chem. 2015 May 14;58(9):3682-92. doi: 10.1021/acs.jmedchem.5b00127. Epub 2015 Mar 17.


The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness of the β-lactam class of antimicrobials. A program was initiated to discover a new series of serine β-lactamase inhibitors containing a boronic acid pharmacophore, with the goal of finding a potent inhibitor of serine carbapenemase enzymes that are currently compromising the utility of the carbapenem class of antibacterials. Potential lead structures were screened in silico by modeling into the active sites of key serine β-lactamases. Promising candidate molecules were synthesized and evaluated in biochemical and whole-cell assays. Inhibitors were identified with potent inhibition of serine carbapenemases, particularly the Klebsiella pneumoniae carbapenemase (KPC), with no inhibition of mammalian serine proteases. Studies in vitro and in vivo show that RPX7009 (9f) is a broad-spectrum inhibitor, notably restoring the activity of carbapenems against KPC-producing strains. Combined with a carbapenem, 9f is a promising product for the treatment of multidrug resistant Gram-negative bacteria.

Publication types

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

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Boronic Acids / chemistry*
  • Boronic Acids / pharmacokinetics
  • Boronic Acids / pharmacology
  • Carbapenems / pharmacology
  • Crystallography, X-Ray
  • Drug Resistance, Bacterial
  • Drug Synergism
  • Gram-Negative Bacteria / drug effects
  • Gram-Negative Bacteria / enzymology
  • Gram-Negative Bacteria / isolation & purification
  • Heterocyclic Compounds, 1-Ring / chemistry*
  • Heterocyclic Compounds, 1-Ring / pharmacokinetics
  • Heterocyclic Compounds, 1-Ring / pharmacology
  • Mice
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • beta-Lactamase Inhibitors / chemistry*
  • beta-Lactamase Inhibitors / pharmacokinetics
  • beta-Lactamase Inhibitors / pharmacology
  • beta-Lactamases


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Boronic Acids
  • Carbapenems
  • Heterocyclic Compounds, 1-Ring
  • RPX7009
  • beta-Lactamase Inhibitors
  • beta-Lactamases
  • carbapenemase

Associated data

  • PDB/4XUX
  • PDB/4XUZ