Bacterial pathogens deploy an arsenal of virulence factors to establish infections and cause disease. Our structural microbiology laboratory uses X-ray crystallography to characterise the 3D structures of virulence proteins in pathogenic bacteria, including surface adhesins, secreted toxins as well as virulence factors foldases. We combine these high-resolution images with biophysical, molecular and biochemical studies to precisely dissect their mechanism of action and then apply this new knowledge for translational applications. In this talk I will present some recent examples from our research program, particularly focusing on virulence factors foldases and bacterial surface adhesins.
Central to bacterial virulence are the disulfide bond (Dsb) forming enzymes, a widespread set of enzymes required for the folding of many virulence proteins. We investigate the structure and function of Dsb enzymes from pathogenic bacteria and our work has uncovered an unexpected diversity in the bacterial disulfide-forming toolbox across bacteria and how these proteins contribute to pathogenesis1. We are also using these proteins for the development of new types of pathoblockers and biotechnology tools.
Another important part of our research investigates autotransporters proteins, the largest group of surface adhesins in Gram-negative bacteria. These proteins play a central role in controlling bacterial interactions; they allow bacteria to aggregate with other bacteria, adhere to human cells, and form biofilms, all key facilitators of bacterial persistence and pathogenesis. Using a multidisciplinary framework that combines X-ray crystallography, extensive biophysical and biochemical techniques, immunoassays and cellular assays, we have defined the structure and function of a number of autotransporters central for virulence. Our work is uncovering for example how different autotransporter promote bacterial aggregation using subtle variations of a universally conserved self-association mechanism2. We have also shown in atomic detail how these autotransporter adhesins bind epithelial surfaces3. Using this new knowledge, we have successfully developed molecules with anti-biofilm activity that disrupt autotransporter function in bacteria.