Structural and Biochemical Features of OXA-517: a Carbapenem and Expanded-Spectrum Cephalosporin Hydrolyzing OXA-48 Variant.
(2023) Antimicrobial Agents and Chemotherapy — Vol. 67, n° 2, p. e0109522 [1-17] (2023)
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Naas, Thierry 
- Abstract
- 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 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 gene was located on a ca. 31-kb plasmid identical to the prototypical IncL -carrying plasmid except for an IS-mediated deletion of 30.7-kb in the 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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Dabos, L., Raczynska, J. E., Bogaerts, P., Zavala, A., Girlich, D., Bonnin, R. A., Dortet, L., Peyrat, A., Retailleau, P., Iorga, B. I., Jaskólski, M., Glupczynski, G., & Naas, T. (2023). Structural and Biochemical Features of OXA-517: a Carbapenem and Expanded-Spectrum Cephalosporin Hydrolyzing OXA-48 Variant. Antimicrobial Agents and Chemotherapy, 67(2), e0109522 [1-17]. https://doi.org/10.1128/aac.01095-22 (Original work published 2023)