Melioidosis is a disease prominent in Southeast Asia and northern Australia, caused by Burkholderia pseudomallei. It has stubbornly high mortality and a complex, protracted treatment regimen.
DiSulfide Bond (DSB) proteins are a family of foldases that catalyse the oxidative folding of virulence proteins in many bacterial species. There is now overwhelming evidence that DSB proteins play a pivotal role in bacterial pathogenesis. We have found previously that disulfide bond protein A (DsbA) is required for B. pseudomallei to cause disease. We now demonstrate that a second enzyme, the membrane protein Disulfide Bond protein B (DsbB) is DsbA’s partner and is highly conserved among B. pseudomallei strains. A panel of B. pseudomallei dsbB deletion strains were phenotypically diverse with in vitro assays that assess hallmarks of virulence, but critically irrespective of in vitro virulence phenotypes, two deletion strains were attenuated in a BALB/c mouse model of infection. We have also solved a crystal structure of a DsbB-derived peptide complexed with BpsDsbA providing the first molecular characterization of the interaction of these two proteins.
This work validates DSB proteins as mediators of virulence in B. pseudomallei, contributes to our broader understanding of DSB redox biology and structure, and will support antimicrobial drug design against this important family of bacterial virulence targets.