Structural basis for carbapenemase activity of the OXA-23 β-lactamase from Acinetobacter baumannii

Chem Biol. 2013 Sep 19;20(9):1107-15. doi: 10.1016/j.chembiol.2013.07.015. Epub 2013 Sep 5.

Abstract

Dissemination of Acinetobacter baumannii strains harboring class D β-lactamases producing resistance to carbapenem antibiotics severely limits our ability to treat deadly Acinetobacter infections. Susceptibility determination in the A. baumannii background and kinetic studies with a homogeneous preparation of OXA-23 β-lactamase, the major carbapenemase present in A. baumannii, document the ability of this enzyme to manifest resistance to last-resort carbapenem antibiotics. We also report three X-ray structures of OXA-23: apo OXA-23 at two different pH values, and wild-type OXA-23 in complex with meropenem, a carbapenem substrate. The structures and dynamics simulations reveal an important role for Leu166, whose motion regulates the access of a hydrolytic water molecule to the acyl-enzyme species in imparting carbapenemase activity.

Publication types

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

MeSH terms

  • Acinetobacter baumannii / drug effects
  • Acinetobacter baumannii / enzymology*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Binding Sites
  • Carbapenems / chemistry
  • Carbapenems / metabolism
  • Carbapenems / pharmacology
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Resistance, Bacterial / drug effects
  • Hydrogen-Ion Concentration
  • Kinetics
  • Meropenem
  • Molecular Dynamics Simulation
  • Protein Structure, Tertiary
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Thienamycins / chemistry
  • Thienamycins / metabolism
  • beta-Lactamases / chemistry
  • beta-Lactamases / genetics
  • beta-Lactamases / metabolism*

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Carbapenems
  • Recombinant Proteins
  • Thienamycins
  • beta-lactamase OXA-2
  • beta-lactamase OXA-23
  • beta-Lactamases
  • carbapenemase
  • Meropenem

Associated data

  • PDB/4JF4
  • PDB/4JF5
  • PDB/4JF6