Antibiotic resistance in Tuberculosis: Predicting de novo the effect of individual genetic mutations.

Project Overview

Tuberculosis (TB) is now the single largest infectious disease killer globally, with over 1.5 million people dying of the disease in 2014. In common with all infectious diseases, the use of antibiotics of the last 70 years has led to the emergence of resistance.

The cell wall of M.tuberculosis is unusually thick; the consequences of this are that the bacteria grow very slowly, and therefore conventional lab-based diagnostics takes around a month to determine if an infection is resistant, and secondly, there is a comparatively small panel of antibiotics that can be used to treat the disease.

The Modernising Medical Microbiology (MMM) group here at the John Radcliffe Hospital are pioneering the use of genetic sequencing to infer the resistance phenotype of clinical TB cases by examining the bacterial genome for known resistance-causing mutations. The MMM group, through Derrick Crook, is leading the international TB consortium, CRyPTIC, that has been funded by the Wellcome Trust and the Gates Foundation. This large project, which will run until 2021, will collect samples from 100,000+ patients with TB worldwide and, for each, sequence the genome of the pathogen and determine its susceptibility to a panel of antibiotics.

The student will develop a computational method that is able to predict from the structure of the protein encoded by the gene alone (i.e. without reference to existing known clinical cases) whether a mutation is likely to cause resistance or not. The ultimate goal is for methods like this to be incorporated into a genetics-based clinical microbiology, giving it a truly predictive capability, so that when novel or rare mutations in TB are encountered (as they will be), a prediction of the likelihood that it causes resistance can be fed back to the clinician.

Early work in the group has shown that mutations which cause the antibiotic to bind less well to their target protein, whilst not significantly affecting how well the natural substrate binds, are resistant, and therefore calculating how the mutation affects the binding free energies of both the antibiotic and the substrate is one route to predicting resistance. The student will be free, however, to choose or develop the most appropriate method that is able to solve this problem, under the guidance of both supervisors.

This is a highly interdisciplinary project and therefore no candidate is expected to have all the skills and knowledge necessary at the start; these will be gained through the training opportunities outlined below.

Training Opportunities

 The student will be exposed to and trained in

Depending on the student's interests, there would be also potential to explore (see bashthebug.net)

The student would need to collaborate and work with a large virtual team made up of

The student would be encouraged to collaborate with the growing number of international partners in CRyPTIC and take advantage of the numerous training courses available through the department and university.

Theme

Immunology & Infectious Disease and Protein Science & Structural Biology

Admissions

Project reference number: 872

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor (Ann) Sarah Walker Experimental Medicine Division Oxford University, John Radcliffe Hospital GBR sarah.walker@ndm.ox.ac.uk
Dr Philip Fowler Experimental Medicine Division Oxford University, John Radcliffe Hospital GBR philip.fowler@ndm.ox.ac.uk

There are no publications listed for this DPhil project.