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Biochemical-genetic characterization and distribution of OXA-22, a chromosomal and inducible class D beta-lactamase from Ralstonia (Pseudomonas) pickettii.

ABSTRACT: From genomic DNA of Ralstonia pickettii isolate PIC-1, a beta-lactamase gene was cloned that encodes the oxacillinase OXA-22. It differs from known oxacillinases, being most closely related to OXA-9 (38% amino acid identity). The hydrolytic spectrum of OXA-22 is limited mostly to benzylpenicillin, cloxacillin, and restricted-spectrum cephalosporins. OXA-22-like genes were identified as single chromosomal copies in five other R. pickettii clinical isolates. The expression of OXA-22-like beta-lactamases was inducible in R. pickettii.

SUBMITTER: Nordmann P

PROVIDER: S-EPMC90041 | biostudies-literature | 2000 Aug

REPOSITORIES: biostudies-literature

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Biochemical-genetic characterization and distribution of OXA-22, a chromosomal and inducible class D beta-lactamase from Ralstonia (Pseudomonas) pickettii.

Nordmann P P Poirel L L Kubina M M Casetta A A Naas T T

Antimicrobial agents and chemotherapy 20000801 8

From genomic DNA of Ralstonia pickettii isolate PIC-1, a beta-lactamase gene was cloned that encodes the oxacillinase OXA-22. It differs from known oxacillinases, being most closely related to OXA-9 (38% amino acid identity). The hydrolytic spectrum of OXA-22 is limited mostly to benzylpenicillin, cloxacillin, and restricted-spectrum cephalosporins. OXA-22-like genes were identified as single chromosomal copies in five other R. pickettii clinical isolates. The expression of OXA-22-like beta-lact ...[more]

PMID: 10898703

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Project description:Abstract Background Recently, we described a collection of ST298 Pseudomonas aeruginosa (PA) isolates that caused a prolonged epidemic of XDR infections. Many of these contain derivatives of a new plasmid, pPABL048, that harbors an MDR integron, in1697. In1697 contains a series of antimicrobial resistance (AMR) genes, one of which is the class D β-lactamase blaOXA-10. Variants of blaOXA-10 have been described that confer both extended-spectrum β-lactamase (ESBL) and carbapenemase activity. Methods Of all ST298 isolates, three were resistant to ceftazidime (CTZ). Genomic comparison of in1697 in CTZ-resistant and CTZ-sensitive strains revealed that all three strains harbored a blaOXA-10 allele with two single nucleotide variations resulting in amino acid changes at positions 153 (F153S) and 157 (G157D). Using the NCBI database, we identified this allele as unique and defined this β-lactamase as OXA-935. OXA-935 shares the G157D variation with OXA-14 which is known to confer resistance to ceftazidime. We sought to characterize the function of OXA-935 and to determine the crystal structures of OXA-14 and OXA-935. Results Deletion of blaOXA-935 phenotypically converted all three strains to CTZ-susceptible. Expression of blaOXA-14 and blaOXA-935 conferred CTZ-resistance to laboratory PA strains PA01 and PA14. Determination of the crystal structures of OXA-14 (PDB code 7L5R) and OXA-935 (PDB code 7L5V) revealed that the F153S variant resulted in increased flexibility in the enzyme’s Ω loop. Conformational changes in the Ω loop likely contributed to the lack of carbamylation at lysine-70 (K70) observed in OXA-935. Carbamylation of K70 is known to be critical for enzymatic activity of class D β-lactamases. Conclusion OXA-935 is very similar to OXA-14; however, comparison revealed that the F153S variant has unique structural features and is functionally distinct. Despite these differences, both enzymes confer high-level CTZ resistance. As we increasingly rely on β-lactam antimicrobial therapy (e.g. ceftazidime, cefepime) and combination (e.g. ceftazidime-avibactam) therapy to treat MDR PA infections, it is critical that we continue to explore the mechanistic basis of β-lactam AMR in an effort to preserve existing treatments and design novel ones. Disclosures All Authors: No reported disclosures

Dataset Information

Biochemical-genetic characterization and distribution of OXA-22, a chromosomal and inducible class D beta-lactamase from Ralstonia (Pseudomonas) pickettii.

Publications

Biochemical-genetic characterization and distribution of OXA-22, a chromosomal and inducible class D beta-lactamase from Ralstonia (Pseudomonas) pickettii.

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