Poster Presentation BacPath 13: Molecular Analysis of Bacterial Pathogens Conference 2015

Bacterial disarmament: DSB proteins as an anti-virulence target in Burkholderia pseudomallei (#125)

Roisin M. McMahon 1 , Philip Ireland 2 , Martin Scanlon 3 , Mitali Sarkar-Tyson 2 , Jennifer Martin 1
  1. Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, QLD, Australia
  2. Defence Science and Technology Laboratory, Porton Down, UK
  3. Department of Medicinal Chemistry, Monash University, Parkville, Melbourne, VIC, Australia

Melioidosis is a human disease endemic in north Australia and South East Asia that is caused by the bacterium Burkholderia pseudomallei. B. pseudomallei is naturally multi-drug resistant and a potential bioweapon. The disease burden of melioidosis is high with fatality rates of ~15-40%.

Current antibiotic treatments for melioidosis are limited, and relatively inefficient. New drugs would mitigate the risk of sole-reliance on current agents and could offer shorter treatments. Of particular interest are antimicrobials that target bacterial virulence rather than bacterial growth as they are anticipated to induce a reduced selection pressure to develop resistance.

DiSulfide Bond (DSB) proteins are a family of foldases that catalyse oxidative folding of bacterial virulence proteins1. We have shown that in Burkholderia pseudomallei deletion of DiSulfide Bond protein A (BpsDsbA) has pleiotropic effects on virulence, and prevents lethal infection in a mousemodel of melioidosis; all animals infected with wild type bacteria die within 40 days of infection, all those infected with the mutant bacteria survive2.This was complemented by the high-resolution crystal structure of BpsDsbA which provided mechanistic insight, and an important framework for ongoing structure guided drug development2.

B. pseudomallei DSB proteins engage in a number of protein-protein interactions that we aim to disrupt using protein crystallography and structure based drug discovery approaches. I will also discuss our current work to structurally and biochemically characterize the interaction between BpsDsbA and its membrane partner protein BpsDsbB as part of ongoing efforts to develop DSB inhibitors in B. pseudomallei

  1. Heras B, Shouldice SR, Totsika M, Scanlon MJ, Schembri MA, Martin JL. 2009. DSB proteins and bacterial pathogenicity. Nat. Rev. Microbiol. 7: 215-225
  2. Ireland PMº, McMahon RMº, Marshall L, Halili M, Furlong E, Tay S, Martin JL, Sarkar-Tyson. 2014. Disarming Burkholderia pseudomallei: structural and functional characterization of a disulfide oxidoreductase (DsbA) required for virulence in vivo. Antioxid Redox Signal. 20: 606-617