Structure-based drug design against a biosecurity pathogen

Coxiella burnetii is the causative agent of Q-fever, a zoonotic disease endemic globally and particularly in the South-West in the UK. C. burnetii is an obligate pathogen of ruminants: in livestock it causes abortions and still-births, with obvious economic consequences. C. burnetii is an opportunistic pathogen of humans with a very low infectious dose. Q-fever causes serious flu-like symptoms. Whilst these are usually self-resolving, some patients require hospital treatment, and some of these go on to suffer serious complications (e.g. myocarditis). C. burnetii is one of the causative agents of the so-called "desert fever" suffered by UK service personal in the Middle East, and has been associated with chronic fatigue syndrome. There is a clear need for effective treatments for C. burnetii. We are part of an ongoing (BBSRC funded) programme to produce a vaccine using the polysaccharide O-antigen of C. burnetii, the best current vaccine candidate. We have identified several of the biosynthetic proteins that support our hypotheses on the biosynthesis. In this project, the student will develop a bioinformatics pipeline to select the most scientifically interesting and potentially druggable proteins from Coxiella biosynthetic pathways. The student will determine the structure of these proteins, and will test the wild-type enzyme and selected mutants for enzyme activity. The student will use modelling software to study the enzymes using molecular dynamics and quantum mechanical simulations to support proposed enzymatic mechanisms. These data will then be used to model drug binding to the proteins as a first step towards drug development. This work will therefore have both academic and practical outputs.