Article ; Online: Structural and dynamic features of Acinetobacter baumannii OXA-66 β-lactamase explain its stability and evolution of novel variants.
2024 , Page(s) 168603
Abstract: OXA-66 is a member of the OXA-51 subfamily of class D β -lactamases native to the Acinetobacter genus that includes Acinetobacter baumannii, one of the ESKAPE pathogens and a major cause of drug-resistant nosocomial infections. Although both wild type ... ...
Abstract | OXA-66 is a member of the OXA-51 subfamily of class D β -lactamases native to the Acinetobacter genus that includes Acinetobacter baumannii, one of the ESKAPE pathogens and a major cause of drug-resistant nosocomial infections. Although both wild type OXA-66 and OXA-51 have low catalytic activity, they are ubiquitous in the Acinetobacter genomes. OXA-51 is also remarkably thermostable. In addition, newly emerging, single and double amino acid variants show increased activity against carbapenems, indicating that the OXA-51 subfamily is growing and gaining clinical significance. In this study, we used molecular dynamics simulations, X-ray crystallography, and thermal denaturation data to examine and compare the dynamics of OXA-66 WT and its gain-of-function variants: I129L (OXA-83), L167V (OXA-82), P130Q (OXA-109), P130A, and W222L (OXA-234). Our data indicate that OXA-66 WT also has a high melting temperature, and its remarkable stability is due to an extensive and rigid hydrophobic bridge formed by a number of residues around the active site and harbored by the three loops, P, Ω, and β5-β6. Compared to the WT enzyme, the mutants exhibit higher flexibility only in the loop regions, and are more stable than other robust carbapenemases, such as OXA-23 and OXA-24/40. All the mutants show increased rotational flexibility of residues I129 and W222, which allows carbapenems to bind. Overall, our data support the hypothesis that structural features in OXA-51 and OXA-66 promote evolution of multiple highly stable variants with increased clinical relevance in A. baumannii. |
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Language | English |
Publishing date | 2024-05-08 |
Publishing country | Netherlands |
Document type | Journal Article |
ZDB-ID | 80229-3 |
ISSN | 1089-8638 ; 0022-2836 |
ISSN (online) | 1089-8638 |
ISSN | 0022-2836 |
DOI | 10.1016/j.jmb.2024.168603 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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