7N1M

Crystal Structure of the Class D Beta-lactamase OXA-935 from Pseudomonas aeruginosa, Orthorhombic Crystal Form

Summary for 7N1M

• Entry DOI: 10.2210/pdb7n1m/pdb
• Descriptor: Beta-lactamase OXA-935, SULFATE ION (3 entities in total)
• Functional Keywords: structural genomics, center for structural genomics of infectious diseases, csgid, class d beta-lactamase, oxa-935, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 57560.21

Authors

Minasov, G.,Shuvalova, L.,Rosas-Lemus, M.,Brunzelle, J.B.,Satchell, K.J.F.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2021-05-27, release date: 2022-07-06, Last modification date: 2024-11-06)

Primary citation

Pincus, N.B.,Rosas-Lemus, M.,Gatesy, S.W.M.,Bertucci, H.K.,Brunzelle, J.S.,Minasov, G.,Shuvalova, L.A.,Lebrun-Corbin, M.,Satchell, K.J.F.,Ozer, E.A.,Hauser, A.R.,Bachta, K.E.R.
Functional and Structural Characterization of OXA-935, a Novel OXA-10-Family beta-Lactamase from Pseudomonas aeruginosa.
Antimicrob.Agents Chemother., 66:e0098522-e0098522, 2022

PubMed Abstract: Resistance to antipseudomonal penicillins and cephalosporins is often driven by the overproduction of the intrinsic β-lactamase AmpC. However, OXA-10-family β-lactamases are a rich source of resistance in Pseudomonas aeruginosa. OXA β-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 , named , 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 restored the sensitivity to ceftazidime, and susceptibility profiling of P. aeruginosa laboratory strains expressing 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 (Ω) loop. Amino acid changes that confer extended spectrum cephalosporinase activity to OXA-10-family β-lactamases are concerning, given the rising reliance on novel β-lactam/β-lactamase inhibitor combinations, such as ceftolozane-tazobactam and ceftazidime-avibactam, to treat MDR P. aeruginosa infections.

PubMed: 36129295
DOI: 10.1128/aac.00985-22

Experimental method

X-RAY DIFFRACTION (1.96 Å)