Structural Biology of Infection

Summary Current work revolves around understanding how CDC toxins penetrate membranes.

Project Details

We have made major contributions to our understanding of how bacterial pore-forming toxins can pass through the walls of target cells. In recent years this work has expanded into studies of other infectious organisms such as parasites and viruses. An example of our work is:

Protein toxins (with Professor Rod Tweten, University of Oklahoma, USA;  Dr Laurie Comstock, Harvard University, USA)

Pore-forming toxins are promising model systems for understanding the biogenesis, structure and function of membrane channels as well as being potential targets for new antibiotics. One example of our work is perfringolysin O (PFO), a 52 kDa toxin secreted by the gas gangrene bacterium Clostridium perfringens, a member of a family of more than 20 toxins produced by Gram-positive bacteria. This family is often referred to as cholesterol-dependent cytolysins (CDCs) because of their strict requirement for membrane-bound cholesterol for activity. The presumed common mode of action of these toxins involves binding to target cell membranes via cholesterol, insertion into the lipid bilayer of target cells followed by oligomerisation and pore formation leading to cytolysis. However, the details of the molecular mechanism of membrane damage are not known. We have now determined the crystal structures of a number of CDCs. Current work revolves around understanding how CDC toxins penetrate membranes.