Biogenesis of virulence factors

Bacteria utilise folding enzymes to assemble proteins that are essential for cell integrity and to produce functional virulence factors. These foldases include the Dsb family of proteins, which catalyse a key step in the protein-folding pathway: the introduction of disulfide bonds. The Dsb oxidative systems are present in numerous bacterial species and are central mediators of virulence. They play a crucial part in the biogenesis of virulence factors, including proteins associated with adhesion (e.g. fimbriae), host cell manipulation (e.g. toxins) and cellular spread (e.g. flagella). Mutants defective in the Dsb pathways have reduced fitness and attenuated virulence. In this context, we have two major topics that we investigate both of which are aimed at increasing our understanding of the biology of bacterial pathogens.

First we decipher the molecular mechanisms through which a number of bacteria catalyse the oxidative folding of proteins involved in virulence. Our studies have revealed cryptic structural variation among different homologues of these folding catalysts that may play a vital role in their function.

Second, we work towards the development of a new class of antimicrobial agents by inhibiting these redox pathways. We use structural approaches, namely Fragment Based Drug Discovery (FBDD) using X-ray crystallography to identify compounds that bind and inhibit the activity of these crucial enzymes.