Molecular basis of selective inhibition and slow reversibility of avibactam against class D carbapenemases: a structure-guided study of OXA-24 and OXA-48

ACS Chem Biol. 2015 Feb 20;10(2):591-600. doi: 10.1021/cb500703p. Epub 2014 Dec 4.

Abstract

The Class D (or OXA-type) β-lactamases have expanded to be the most diverse group of serine β-lactamases with a highly heterogeneous β-lactam hydrolysis profile and are typically resistant to marketed β-lactamase inhibitors. Class D enzymes are increasingly found in multidrug resistant (MDR) Acinetobacter baumannii, Pseudomonas aeruginosa, and various species of the Enterobacteriaceae and are posing a serious threat to the clinical utility of β-lactams including the carbapenems, which are typically reserved as the drugs of last resort. Avibactam, a novel non-β-lactam β-lactamase inhibitor, not only inhibits all class A and class C β-lactamases but also has the promise of inhibition of certain OXA enzymes, thus extending the antibacterial activity of the β-lactam used in combination to the organisms that produce these enzymes. X-ray structures of OXA-24 and OXA-48 in complex with avibactam revealed the binding mode of this inhibitor in this diverse class of enzymes and provides a rationale for selective inhibition of OXA-48 members. Additionally, various subunits of the OXA-48 structure in the asymmetric unit provide snapshots of different states of the inhibited enzyme. Overall, these data provide the first structural evidence of the exceptionally slow reversibility observed with avibactam in class D β-lactamases. Mechanisms for acylation and deacylation of avibactam by class D enzymes are proposed, and the likely extent of inhibition of class D β-lactamases by avibactam is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Azabicyclo Compounds / pharmacology*
  • Bacterial Proteins / classification*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Binding Sites
  • Crystallization
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactamases / classification*
  • beta-Lactamases / genetics
  • beta-Lactamases / metabolism*

Substances

  • Azabicyclo Compounds
  • Bacterial Proteins
  • Escherichia coli Proteins
  • beta-Lactamase Inhibitors
  • avibactam
  • beta-Lactamases
  • beta-lactamase OXA-24
  • beta-lactamase OXA-48, E coli
  • carbapenemase

Associated data

  • PDB/4WM9
  • PDB/4WMC