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Publication Abstract from PubMed

Resistance to antipseudomonal penicillins and cephalosporins is often driven by the overproduction of the intrinsic beta-lactamase AmpC. However, OXA-10-family beta-lactamases are a rich source of resistance in Pseudomonas aeruginosa. OXA beta-lactamases have a propensity for mutation that leads to extended spectrum cephalosporinase and carbapenemase activity. In this study, we identified isolates from a subclade of the multidrug-resistant (MDR) high risk P. aeruginosa clonal complex CC446 with a resistance to ceftazidime. A genomic analysis revealed that these isolates harbored a plasmid containing a novel allele of bla(OXA-10), named bla(OXA-935), which was predicted to produce an OXA-10 variant with two amino acid substitutions: an aspartic acid instead of a glycine at position 157 and a serine instead of a phenylalanine at position 153. The G157D mutation, present in OXA-14, is associated with the resistance of P. aeruginosa to ceftazidime. Compared to OXA-14, OXA-935 showed increased catalytic efficiency for ceftazidime. The deletion of bla(OXA-935) restored the sensitivity to ceftazidime, and susceptibility profiling of P. aeruginosa laboratory strains expressing bla(OXA-935) revealed that OXA-935 conferred ceftazidime resistance. To better understand the impacts of the variant amino acids, we determined the crystal structures of OXA-14 and OXA-935. Compared to OXA-14, the F153S mutation in OXA-935 conferred increased flexibility in the omega (Omega) loop. Amino acid changes that confer extended spectrum cephalosporinase activity to OXA-10-family beta-lactamases are concerning, given the rising reliance on novel beta-lactam/beta-lactamase inhibitor combinations, such as ceftolozane-tazobactam and ceftazidime-avibactam, to treat MDR P. aeruginosa infections.

Functional and Structural Characterization of OXA-935, a Novel OXA-10-Family beta-Lactamase from Pseudomonas aeruginosa.,Pincus NB, Rosas-Lemus M, Gatesy SWM, Bertucci HK, Brunzelle JS, Minasov G, Shuvalova LA, Lebrun-Corbin M, Satchell KJF, Ozer EA, Hauser AR, Bachta KER Antimicrob Agents Chemother. 2022 Oct 18;66(10):e0098522. doi: , 10.1128/aac.00985-22. Epub 2022 Sep 21. PMID:36129295^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.