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Characterization of the first OXA-10 natural variant with increased carbapenemase activity.

Journal article
Authors Stathis Kotsakis
Carl-Fredrik Flach
Mohammad Razavi
D. G. Joakim Larsson
Published in Antimicrobial agents and chemotherapy
Volume 63
Issue 1
Pages e01817-18
ISSN 1098-6596
Publication year 2018
Published at Institute of Biomedicine, Department of Infectious Medicine
Centre for antibiotic resistance research, CARe
Pages e01817-18
Language en
Links dx.doi.org/10.1128/AAC.01817-18
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Microbiology, Microbiology in the medical area

Abstract

While carbapenem resistance in Gram-negatives is mainly due to production of efficient carbapenemases, β-lactamases with narrower spectrum may also contribute to resistance when combined with additional mechanisms. OXA-10 type class D β-lactamases, previously shown to be weak carbapenemases, could represent such a case. In this study two novel OXA-10 variants were identified as the sole carbapenem hydrolyzing enzymes in meropenem resistant Enterobacteria isolated from hospital waste water and found by NGS to express additional β-lactam resistance mechanisms. The new variants, OXA-655 and OXA-656, were carried by two related IncQ1 broad-host plasmids. Compared to OXA-10 they both harbor a Thr26Met substitution with OXA-655 also baring leucine instead of valine in position 117 of the SAV catalytic motif. Susceptibility profiling of laboratory strains replicating the natural blaOXA plasmids and of recombinant clones expressing OXA-10 and the novel variants in isogenic background indicated that OXA-655 is a more efficient carbapenemase. The carbapenemase activity of OXA-655 is due to the Val117Leu substitution as shown by steady state kinetic experiments where the kcat of meropenem hydrolysis was increased 4-fold. In contrast, OXA-655 has no activity towards oxyimino β-lactams while its catalytic efficiency against oxacillin is significantly reduced. Moreover, the Val117Leu variant is more efficient against temocillin and cefoxitin. Molecular dynamics indicated that Val117Leu affects the 117-Leu155 interaction leading to structural shifts in the active site that may alter carbapenem alignment. The evolutionary potential of OXA-10 enzymes towards carbapenem hydrolysis combined with their spread by promiscuous plasmids indicates that they may pose a future clinical threat.

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