title: Clinical Variants of the Native Class D β-Lactamase of Acinetobacter baumannii Pose an Emerging Threat through Increased Hydrolytic Activity against Carbapenems.
abstract: The threat posed by the chromosomally encoded class D β-lactamase of Acinetobacter baumannii (OXA-51/66) has been unclear, in part because of its relatively low affinity and turnover rate for carbapenems. Several hundred clinical variants of OXA-51/66 have been reported, many with substitutions of active-site residues. We determined the kinetic properties of OXA-66 and five clinical variants with respect to a wide variety of β-lactam substrates. The five variants displayed enhanced activity against carbapenems and in some cases against penicillins, late-generation cephalosporins, and the monobactam aztreonam. Molecular dynamics simulations show that in OXA-66, P130 inhibits the side-chain rotation of I129 and thereby prevents doripenem binding because of steric clash. A single amino acid substitution at this position (P130Q) in the variant OXA-109 greatly enhances the mobility of both I129 and a key active-site tryptophan (W222), thereby facilitating carbapenem binding. This expansion of substrate specificity represents a very worrisome development for the efficacy of β-lactams against this troublesome pathogen.
authors.affiliation: Department of Chemistry, Grand Valley State University, Allendale, Michigan, USA.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Schroder
authors.affiliation: Department of Cell and Molecular Biology, Grand Valley State University, Allendale, Michigan, USA.
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Klamer
authors.affiliation: Department of Biology, Faculty of Arts and Sciences, Artvin Coruh University, Artvin, Turkey.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Saral
authors.affiliation: Department of Cell and Molecular Biology, Grand Valley State University, Allendale, Michigan, USA.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Sugg
authors.affiliation: Department of Chemistry, Grand Valley State University, Allendale, Michigan, USA.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: June
authors.affiliation: Department of Chemistry and Biophysics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Troy
authors.initials: T
authors.lastname: Wymore
authors.affiliation: Department of Cell and Molecular Biology, Grand Valley State University, Allendale, Michigan, USA.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Szarecka
authors.affiliation: Department of Chemistry, Grand Valley State University, Allendale, Michigan, USA leonardd@gvsu.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Leonard
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D019943:Amino Acid Substitution; D015780:Carbapenems / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D006801:Humans; D006868:Hydrolysis; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013379:Substrate Specificity; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D015780:Carbapenems; D001618:beta-Lactamases; C577373:beta-lactamase OXA-51, Acinetobacter baumannii