My MRC Career Development Award is focused on the investigation of the role of disulfide bond formation in Gram-negative bacterial pathogens. Disulfide bonds are ubiquitous covalent linkages which are abundant near the outer surfaces of the cell and are responsible for the folding and stability of numerous proteins. Despite their simplicity, they are formed by dedicated protein systems in all organisms. In Gram-negative bacteria this role is carried out by the Disulfide bond (DSB) formation system which comprises five proteins located in the periplasm or the inner membrane of the bacterial cell and is responsible for the quality control of disulfide bridges in hundreds of protein substrates.
Most factors that allow bacteria to be efficient pathogens are also dependent on the function of this system. Even more importantly, the DSB systems found in pathogens seem to have diversified compared to the systems found in non-pathogenic bacteria. Numerous bacterial pathogens encode multiple copies of the key DSB protein players. This implies an adaptation of the system to efficiently handle substrates related to pathogenesis and this aspect of the DSB system remains hugely understudied. In my lab we are using a bioinformatics approach to identify the DSB systems in all Gram-negative bacteria and detect underlying common traits between the systems of pathogens in order to understand the evolution of this pathway into a virulence aid. We also complement the bioinformatics side of the project with experimental work on variant DSB systems found in Neisseria meningitides, Pseudomonas aeruginosa, and Klebsiella pneumoniae. We are interested in identifying the substrates of each additional atypical analogue of the DSB proteins because this is likely to reveal their role in the pathogenesis of these organisms.