GW4 BioMed MRC DTP PhD Studentship: Dissecting an antibiotic resistance network in the hospital ‘superbug’ Enterococcus faecalis

This project is one of a number that are in competition for funding from the ‘GW4 BioMed MRC Doctoral Training Partnership’ which is offering up to 19 studentships for entry in September/October 2018.

The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities. The training programme has three strands: research skills; professional and career development skills; and opportunities to broaden horizons, which might include placements, research visits, public engagement internships and a mini-MD programme of bespoke clinical exposure.

Supervisory team for this project:
Dr Susanne Gebhard (Bath), Dr Steven Porter (Exeter), Dr Tim Rogers (Bath) and Dr Andrew Preston (Bath)

Project description:

Hospital-acquired infections with Enterococcus bacteria impose a significant public health burden, with ca. 5000 cases of bacteraemia reported in the UK each year and an estimated mortality rate of 20%. Enterococci form a natural component of the human gut microflora. Infections usually arise following treatment of a patient for an unrelated infection, and this is because enterococci possess a striking degree of intrinsic drug resistance. While most bacteria within a patient receiving antibiotics die, enterococci can often thrive, which in turn sharply increases the risk for enterococcal infections. Past studies of drug resistance in enterococci have mostly focussed on the antibiotic vancomycin, which is commonly used to treat such infections, and we now have an excellent understanding of the specific resistance mechanisms involved. However, we know surprisingly little about the molecular basis for the intrinsic resistance of the bacteria against many other antibiotics. Considering that this generic resistance is what provides enterococci with the opportunity to cause disease, addressing this question is timely and highly relevant.

This studentship project is aimed at gaining a molecular and systems level understanding of the response of Enterococcus faecalis to antibiotics that target the cell envelope. Building on previous work from the Gebhard lab and the literature, the candidate will identify candidate regulators and resistance genes, and experimentally investigate the signalling pathways that control the cell envelope stress response of E. faecalis. To maximise success and identify the complete regulatory network, the student will apply a two-pronged approach combining random and targeted mutagenesis. Candidate regulators will be confirmed by loss of target gene regulation and resistance. We have recently shown that antibiotic resistance can be organised in complex hierarchical networks that utilise active redundancy between individual resistance determinants to compensate for failure of individual components. The student will therefore analyse any identified regulators for cross-communication and hierarchical organisation using biochemistry, genetics and mathematical modelling. The broad expertise of the supervisory team will ensure cross-cutting training for the candidate in both practical and theoretical state-of-the-art methodology. A detailed understanding of the systems level organisation of the antibiotic stress response of E. faecalis may ultimately allow the identification of an Achilles’ heel that can be exploited for the development of targeted therapeutic strategies. Contacts are in place to a team of clinicians in Denmark who can test the relevance of the findings, e.g. by examining their epidemiological data for prevalence and potential pathoadaptive mutations in the key regulators, which will provide immediate application of this study in a clinical context.

IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form. More information on the application process may be found here: http://www.gw4biomed.ac.uk/projects-2/for-students/

APPLICATIONS OPEN ON 25 SEPTEMBER AND CLOSE AT 17:00 ON 24 NOVEMBER 2017.

You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Bath.