Structural and biochemical features of OXA-517: a Carbapenem and expanded-spectrum Cephalosporin hydrolyzing OXA-48 variant - CEA - Université Paris-Saclay Accéder directement au contenu
Article Dans Une Revue Antimicrobial Agents and Chemotherapy Année : 2023

Structural and biochemical features of OXA-517: a Carbapenem and expanded-spectrum Cephalosporin hydrolyzing OXA-48 variant

Pierre Bogaerts
  • Fonction : Auteur
Bogdan Iorga
Youri Glupczynski
  • Fonction : Auteur

Résumé

OXA-48-producing Enterobacterales have now widely disseminated throughout the world. Several variants have now been reported, differing by just a few amino-acid substitutions or deletions, mostly in the region of the loop β5-β6. As OXA-48 hydrolyzes carbapenems but lacks significant expanded-spectrum cephalosporin (ESC) hydrolytic activity, ESCs were suggested as a therapeutic option. Here, we have characterized OXA-517, a natural variant of OXA-48- with an Arg214Lys substitution and a deletion of Ile215 and Glu216 in the β5-β6 loop, capable of hydrolyzing at the same time ESC and carbapenems. MICs values of E. coli expressing blaOXA-517 gene revealed reduced susceptibility to carbapenems (similarly to OXA-48) and resistance to ESCs. Steady-state kinetic parameters revealed high catalytic efficiencies for ESCs and carbapenems. The blaOXA-517 gene was located on a ca. 31-kb plasmid identical to the prototypical IncL blaOXA-48-carrying plasmid except for an IS1R-mediated deletion of 30.7-kb in the tra operon. The crystal structure of OXA-517, determined to 1.86 Å resolution, revealed an expanded active site compared to that of OXA-48, which allows for accommodation of the bulky ceftazidime substrate. Our work illustrates the remarkable propensity of OXA-48-like carbapenemases to evolve through mutation/deletion in the β5-β6 loop to extend its hydrolysis profile to encompass most β-lactam substrates.
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Dates et versions

hal-03966994 , version 1 (01-02-2023)

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Laura Dabos, Joanna Raczynska, Pierre Bogaerts, Agustin Zavala, Delphine Girlich, et al.. Structural and biochemical features of OXA-517: a Carbapenem and expanded-spectrum Cephalosporin hydrolyzing OXA-48 variant. Antimicrobial Agents and Chemotherapy, 2023, 67 (2), pp.e0109522. ⟨10.1128/aac.01095-22⟩. ⟨hal-03966994⟩
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