Clinical variants of the native class d beta-lactamase of acinetobacter baumannii pose an emerging threat through ıncreased hydrolytic activity against carbapenems
AuthorSchroder, Emma C.
Klamer, Zachary L.
Sugg, Kyle A.
June, Cynthia M.
Leonard, David A.
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CitationSchroder, E. C., Klamer, Z. L., Saral, A., Sugg, K. A., June, C. M., Wymore, T., ... & Leonard, D. A. (2016). Clinical variants of the native class D β-lactamase of Acinetobacter baumannii pose an emerging threat through increased hydrolytic activity against carbapenems. Antimicrobial agents and chemotherapy, 60(10), 6155-6164, doi.10.1128/AAC.01277-16.
The threat posed by the chromosomally encoded class D beta-lactamase of Acinetobacter baumannii (OXA-51/66) has been unclear, in part because of its relatively low affinity and turnover rate for carbapenems. Several hundred clinical variants of OXA51/66 have been reported, many with substitutions of active-site residues. We determined the kinetic properties of OXA-66 and five clinical variants with respect to a wide variety of beta-lactam substrates. The five variants displayed enhanced activity against carbapenems and in some cases against penicillins, late-generation cephalosporins, and the monobactam aztreonam. Molecular dynamics simulations show that in OXA-66, P130 inhibits the side-chain rotation of I129 and thereby prevents doripenem binding because of steric clash. A single amino acid substitution at this position (P130Q) in the variant OXA-109 greatly enhances the mobility of both I129 and a key active-site tryptophan (W222), thereby facilitating carbapenem binding. This expansion of substrate specificity represents a very worrisome development for the efficacy of beta-lactams against this troublesome pathogen.