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.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acinetobacter baumannii / drug effects
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Acinetobacter baumannii / enzymology*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / metabolism
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Anti-Bacterial Agents / pharmacology
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Bacterial Proteins / chemistry
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Bacterial Proteins / metabolism*
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Binding Sites
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Carbapenems / chemistry
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Carbapenems / metabolism
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Carbapenems / pharmacology
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Catalytic Domain
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Crystallography, X-Ray
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Drug Resistance, Bacterial / drug effects
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Hydrogen-Ion Concentration
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Kinetics
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Meropenem
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Molecular Dynamics Simulation
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Protein Structure, Tertiary
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Thienamycins / chemistry
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Thienamycins / metabolism
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beta-Lactamases / chemistry
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beta-Lactamases / genetics
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beta-Lactamases / metabolism*
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Carbapenems
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Recombinant Proteins
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Thienamycins
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beta-lactamase OXA-2
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beta-lactamase OXA-23
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beta-Lactamases
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carbapenemase
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Meropenem
Associated data
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PDB/4JF4
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PDB/4JF5
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PDB/4JF6