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Clinical variants of the native class d beta-lactamase of acinetobacter baumannii pose an emerging threat through ıncreased hydrolytic activity against carbapenems
(Amer Soc Microbiology, 2016) Schroder, Emma C.; Klamer, Zachary L.; Saral, Ayşegül; Sugg, Kyle A.; June, Cynthia M.; Wymore, Troy; Szarecka, Agnieszka; Leonard, David A.
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.