title: 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.affiliation: Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, CA 94025, USA. Electronic address: csmith@slac.stanford.edu.
authors.forename: Clyde A
authors.initials: CA
authors.lastname: Smith
authors.forename: Nuno Tiago
authors.initials: NT
authors.lastname: Antunes
authors.forename: Nichole K
authors.initials: NK
authors.lastname: Stewart
authors.forename: Marta
authors.initials: M
authors.lastname: Toth
authors.forename: Malika
authors.initials: M
authors.lastname: Kumarasiri
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Vakulenko
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000201:enzymology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D015780:Carbapenems / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D000077731:Meropenem; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013845:Thienamycins / Q000737:chemistry / Q000378:metabolism; D001618:beta-Lactamases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; D011994:Recombinant Proteins; D013845:Thienamycins; C039404:beta-lactamase OXA-2; C466679:beta-lactamase OXA-23; D001618:beta-Lactamases; C063912:carbapenemase; D000077731:Meropenem