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

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.

• Authors: Clyde A Smith, Nuno Tiago Antunes, Nichole K Stewart, Marta Toth, Malika Kumarasiri, Mayland Chang, Shahriar Mobashery, Sergei B Vakulenko
• Journal: Chemistry & biology (Chem Biol) Vol. 20 Issue 9 Pg. 1107-15 (Sep 19 2013) ISSN: 1879-1301 [Electronic] United States
• PMID: 24012371 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

• Acinetobacter baumannii (drug effects, enzymology)
• Anti-Bacterial Agents (chemistry, metabolism, pharmacology)
• Bacterial Proteins (chemistry, metabolism)
• Binding Sites
• Carbapenems (chemistry, metabolism, 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, chemistry, genetics)
• Thienamycins (chemistry, metabolism)
• beta-Lactamases (chemistry, genetics, metabolism)