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Identification of the novel class D β-lactamase OXA-679 involved in carbapenem resistance in Acinetobacter calcoaceticus

 
: Tietgen, M.; Kramer, J.S.; Brunst, S.; Djahanschiri, B.; Wohra, S.; Higgins, P.G.; Weidensdorfer, M.; Riedel-Christ, S.; Pos, K.M.; Gonzaga, A.; Steglich, M.; Nübel, U.; Ebersberger, I.; Proschak, E.; Göttig, S.

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Journal of antimicrobial chemotherapy : JAC 74 (2019), Nr.6, S.1494–1502
ISSN: 0305-7453
ISSN: 1460-2091
Englisch
Zeitschriftenaufsatz
Fraunhofer IME ()

Abstract
Objectives: The aim of this study was to characterize the Acinetobacter calcoaceticus clinical isolate AC 2117 with the novel carbapenem-hydrolysing class D β-lactamase (CHDL) OXA-679. Methods: Identification of the species and β-lactamases was verified by genome sequencing (PacBio) and phylogenetic analyses. Antibiotic susceptibility of AC 2117 and transformants harbouring cloned blaOXA-679 was evaluated using antibiotic gradient strips and microbroth dilution. OXA-679 was purified heterologously and kinetic parameters were determined using spectrometry or isothermal titration calorimetry. The impact of OXA-679 production during imipenem therapy was evaluated in the Galleria mellonella infection model. Results: Sequencing of the complete genome of the clinical A. calcoaceticus isolate AC 2117 identified a novel CHDL, termed OXA-679. This enzyme shared sequence similarity of 71% to each of the families OXA-143 and OXA-24/40. Phylogenetic analyses revealed that OXA-679 represents a member of a new OXA family. Cloning and expression of blaOXA-679 as well as measurement of kinetic parameters revealed the effective hydrolysis of carbapenems which resulted in reduced susceptibility to carbapenems in Escherichia coli and A. calcoaceticus, and high-level carbapenem resistance in Acinetobacter baumannii. Infection of larvae of G. mellonella with a sublethal dose of blaOXA-679-expressing A. baumannii could not be cured by high-dose imipenem therapy, indicating carbapenem resistance in vivo. Conclusions: We identified blaOXA-679 in a clinical A. calcoaceticus isolate that represents a member of the new OXA-679 family and that conferred high-level carbapenem resistance in vitro and in vivo.

: http://publica.fraunhofer.de/dokumente/N-586858.html