Disarming Burkholderia pseudomallei: structural and functional characterization of a disulfide oxidoreductase (DsbA) required for virulence in vivo

Ireland, Philip M., McMahon, Róisín M., Marshall, Laura E., Halili, Maria, Furlong, Emily, Tay, Stephanie, Martin, Jennifer L. and Sarkar-Tyson, Mitali (2013) Disarming Burkholderia pseudomallei: structural and functional characterization of a disulfide oxidoreductase (DsbA) required for virulence in vivo. Antioxidants & Redox Signaling, Fast Track 1-12. doi:10.1089/ars.2013.5375

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Author Ireland, Philip M.
McMahon, Róisín M.
Marshall, Laura E.
Halili, Maria
Furlong, Emily
Tay, Stephanie
Martin, Jennifer L.
Sarkar-Tyson, Mitali
Title Disarming Burkholderia pseudomallei: structural and functional characterization of a disulfide oxidoreductase (DsbA) required for virulence in vivo
Formatted title
Disarming Burkholderia pseudomallei: structural and functional characterization of a disulfide oxidoreductase (DsbA) required for virulence in vivo
Journal name Antioxidants & Redox Signaling   Check publisher's open access policy
ISSN 1523-0864
1557-7716
Publication date 2013-07-31
Sub-type Article (original research)
DOI 10.1089/ars.2013.5375
Volume Fast Track
Start page 1
End page 12
Total pages 12
Place of publication New Rochelle, NY, United States
Publisher Mary Ann Liebert, Publishers
Language eng
Formatted abstract
Aims: The intracellular pathogen Burkholderia pseudomallei causes the disease melioidosis, a major source of morbidity and mortality in southeast Asia and northern Australia. The need to develop novel antimicrobials is compounded by the absence of a licensed vaccine and the bacterium's resistance to multiple antibiotics. In a number of clinically relevant Gram-negative pathogens, DsbA is the primary disulfide oxidoreductase responsible for catalyzing the formation of disulfide bonds in secreted and membrane-associated proteins. In this study, a putative B. pseudomallei dsbA gene was evaluated functionally and structurally and its contribution to infection assessed.

Results: Biochemical studies confirmed the dsbA gene encodes a protein disulfide oxidoreductase. A dsbA deletion strain of B. pseudomallei was attenuated in both macrophages and a BALB/c mouse model of infection and displayed pleiotropic phenotypes that included defects in both secretion and motility. The 1.9 Å resolution crystal structure of BpsDsbA revealed differences from the classic member of this family Escherichia coli DsbA, in particular within the region surrounding the active site disulfide where EcDsbA engages with its partner protein E. coli DsbB, indicating that the interaction of BpsDsbA with its proposed partner BpsDsbB may be distinct from that of EcDsbA-EcDsbB.

Innovation: This study has characterized BpsDsbA biochemically and structurally and determined that it is required for virulence of B. pseudomallei.

Conclusion: These data establish a critical role for BpsDsbA in B. pseudomallei infection, which in combination with our structural characterization of BpsDsbA will facilitate the future development of rationally designed inhibitors against this drug-resistant organism.
Keyword Disulfide oxidoreductase
Crystal structure
Virulence
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Online Ahead of Editing: July 31, 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 16 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 24 Dec 2013, 18:46:00 EST by Roisin Mcmahon on behalf of Institute for Molecular Bioscience