Virulence Factor Trafficking Pathways in Bacteria

The export of proteins by bacteria is a critical process that is essential for their survival and for the delivery of virulence factors during pathogenesis. The proposal aims to investigate two key pathways by which the model pathogen Escherichia coli transports proteins. The Tat pathway is a very unusual protein transport system that exports pre- folded proteins across the bacterial inner membrane. It is essential for the virulence of E. coli and several other pathogens. <P>

The project aims to understand the structure of the Tat machinery and how it might operate. I will design screens aimed to determine when the Tat system is inactivated, that can be adapted to screen for new antimicrobial drugs. In collaboration with Dr Christoph Tang (Imperial College, London), I wish to elucidate the virulence factors that are delivered by the E. coli Tat pathway and that are responsible for pathogenicity in the rat model. <P> The outer membrane of Gram negative bacteria is the major barrier to the outside world, and is one of the major factors that protects pathogenic bacteria from killing by the hosts immune system. It is essential for bacterial viability. Many proteins and virulence factors are embedded within, or must pass across this membrane. The project will investigate the pathway by which outer membrane proteins are assimilated into the membrane. <P>I will focus on a major new protein, Omp85, that is apparently required for the insertion of an important class of outer membrane proteins. I aim to elucidate the structure of the Omp85 complex, which will ultimately aid the rational design of antimicrobial compounds to block its function. In collaboration with Prof George Georgiou (University of Texas) and Prof David Richardson (University of East Anglia) I will design screens to investigate whether there are other protein factors and pathways required for the assembly of proteins onto the outer bacterial envelope.