Bacterial modification of carbohydrates; structural and functional analysis of a key virulence strategy.

Many bacterial pathogens share a common mechanism for enhancing virulence and persistence; they produce enzymes that modify carbohydrates on the bacterial cell surface. The modification may aid evasion of the immune system (for example modification of the O-antigen in Salmonella sp.), enhance biofilm formation (Staphylococcus aureus) or provide protection from osmotic stress (Escherichia coli); inhibiting these enzymes could lead to new antibiotics. With a view to developing these proteins as potential new therapeutic targets, there are many questions that need to be answered regarding the relationship between structure and function. The aim of this application is to investigate a member of this protein family, OpgC, that succinylates periplasmic glucans in Gram-negative bacterial pathogens. The project will employ an interdisciplinary approach and cutting edge techniques in structural biology, biophysics and molecular microbiology. Like many current drug targets, OpgC is an integral membrane protein thus this project will also provide valuable experience in techniques for working with these challenging proteins. You will receive training in recombinant protein, including membrane protein, expression and purification, the development of functional assays for membrane proteins using novel acyl donor mimics and biophysical/structural characterisation including, as appropriate, NMR spectroscopy and X-ray crystallography. The Technology Facility in the Department of Biology also houses a wide range of facilities including state-of- the-art mass spectrometry for characterising modified substrates. Lab meetings, seminar series, minisymposia and the opportunity to participate in and develop outreach activities will help you develop a broad range of scientific and transferable skills. There is a vibrant PhD community that hosts events like Coffee and Careers. You will be co-supervised and will carry the work out in labs specializing in biochemistry, structural biology and microbiology. This project is suitable for applicants with a strong background and interest in biochemistry and an overall interest in the molecular basis of bacterial pathogenesis.