Substrate Specificity of OXA-48 after β5-β6 Loop Replacement.

ACS Infectious Diseases
Laura DabosThierry Naas

Abstract

OXA-48 carbapenemase has rapidly spread in many countries worldwide with several OXA-48-variants being described, differing by a few amino acid (AA) substitutions or deletions, mostly in the β5-β6 loop. While single AA substitutions have only a minor impact on OXA-48 hydrolytic profiles, others with 4 AA deletions result in loss of carbapenem hydrolysis and gain of expanded-spectrum cephalosporin (ESC) hydrolysis. We have replaced the β5-β6 loop of OXA-48 with that of OXA-18, a clavulanic-acid inhibited oxacillinase capable of hydrolyzing ESCs but not carbapenems. The hybrid enzyme OXA-48Loop18 was able to hydrolyze ESCs and carbapenems (although with a lower kcat), even though the β5-β6 loop was longer and its sequence quite different from that of OXA-48. The kinetic parameters of OXA-48Loop18 were in agreement with the MIC values. X-ray crystallography and molecular modeling suggest that the conformation of the grafted loop allows the binding of bulkier substrates, unlike that of the native loop, expanding the hydrolytic profile. This seems to be due not only to differences in AA sequence, but also to the backbone conformation the loop can adopt. Finally, our results provide further experimental evidence for the role of the β...Continue Reading

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Citations

Jan 26, 2021·ACS Infectious Diseases·Vlatko StojanoskiTimothy Palzkill
Mar 24, 2021·Antimicrobial Agents and Chemotherapy·Viivi H A HirvonenMarc W van der Kamp
Apr 30, 2021·MSphere·Christopher FröhlichHanna-Kirsti S Leiros

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