MRC DiMeN Doctoral Training Partnership: Modelling antibiotic resistance in chronic Pseudomonas aeruginosa infections

Cystic Fibrosis (CF) is the most common genetically-inheritable life-threatening disease amongst Caucasians.  Patients with CF are susceptible to chronic lung infections, most commonly caused by the bacterium Pseudomonas aeruginosa, and these infections are responsible for most of the morbidity and mortality associated with the disease.   CF patients are regularly treated with a cocktail of drugs, including antibiotics.  Aggressive antibiotic therapy is required when patients suffer periodic pulmonary exacerbations, usually with two antibiotics for different bacterial target sites.

Antimicrobial resistance (AMR) has become a global challenge with P. aeruginosa being identified by the WHO as one of the top three priority pathogens.  Antibiotic stewardship (appropriate use of existing drugs) is crucial.  In CF, the choice of antibiotics is often not based on strong evidence, and little is known about whether certain treatments may be less desirable in terms of efficacy or driving resistance, including “collateral” resistance (i.e. resistance to antibiotics other than those used). 

The studentship represents a collaboration between researchers at the Universities of Liverpool and Sheffield, to model the impact of antibiotic treatment regime on long-term (collateral) resistance. In this project we will test the hypothesis that antibiotic treatment against P. aeruginosa can be optimised to limit long term resistance with a range of clinically relevant antibiotics. We will achieve this through three aims:

1.         To perform experimental in vitro evolution in an artificial sputum medium to determine the impact of treatment on resistance in P. aeruginosa. 

2.         To utilise population biology and mathematical modelling to study the wider impact of each treatment regime on long term infections. This will utilise a combination of phenotypic and genetic data. 

3.         To study the evolution of resistance in existing patient sputum samples from a clinical trial in people with CF.

This project would provide extensive training in P. aeruginosa biology, genomics and in vitro, population and mathematical modelling (supported by all supervisors). This project is a clear example of an interdisciplinary approach to tackle a major issue in healthcare, although a maths background is not essential for this project.

CF is a condition that requires the ultimate personalized medicine. This would be addressed by determining the impact of existing antibiotics in this setting and developing models for the impact of long-term antibiotic use on resistance.

Supervisor details:

Dr J Fothergill https://www.liverpool.ac.uk/infection-and-global-health/staff/jo-fothergill/  @JoJoFoth 

Dr Dylan Childs https://www.sheffield.ac.uk/biosciences/people/aps-staff/academic/dylan-childs

Dr K Sharkey https://www.liverpool.ac.uk/mathematical-sciences/staff/kieran-sharkey/

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

https://bit.ly/3lQXR8A