7n1m
From Proteopedia
Crystal Structure of the Class D Beta-lactamase OXA-935 from Pseudomonas aeruginosa, Orthorhombic Crystal Form
Structural highlights
FunctionBLO11_PSEAI Hydrolyzes carbenicillin, oxacillin and cephalosporin. Does not hydrolyze cefoxitin or carbapenems. Publication Abstract from PubMedResistance 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. See AlsoReferences
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