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 18 studentships for entry in September 2020.
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.
Lead supervisor: Dr Brian Jones, Department of Biology & Biochemistry, University of Bath
Co-supervisors: Prof Eshwar Mahenthiralingam (Cardiff), Dr Mark Sutton (Public Health England) and Dr Emma Denham (Bath)
Efflux systems are molecular “pumps” that remove toxic substances from cells. They play important roles in antimicrobial resistance and have an emerging role in biofilm formation. Biofilms are surface associated bacterial communities which are intrinsically resistant to antimicrobials. Up to 80% of infections may involve biofilm formation which is a major barrier to successful treatment. We have recently shown that efflux systems are important for biofilm formation in several bacterial pathogens, and also confer resistance to disinfectants widely used in hospitals. This highlights efflux systems as viable targets for the development of new antibiofilm agents to combat AMR. To realise this goal we will develop a greater fundamental understanding of the role efflux systems play in biofilm formation, their integration with gene networks that govern this process, and identify compounds that can potentially act as efflux-inhibitors and antibiofilm agents.
AIMS & OVERVIEW:
This project will define the role of efflux systems in biofilm formation, using the urinary tract pathogen Proteus mirabilis as a clinically relevant model organism. P. mirabilis forms extensive crystalline biofilms that block catheters leading to serious complications including septicaemia. Our hypothesis is that efflux systems have a waste management and regulatory role in biofilm formation, and that drugs already used in human medicine can be repurposed as efflux-inhibitors and anti-biofilm agents.
The project will be a collaboration with Public Health England, providing interdisciplinary training with experts from the National Infections Service.
Genomic and bioinformatic approaches will be used to characterise a panel of ~100 P. mirabilis clinical isolates, and identify the pool of efflux systems and associated regulatory genes encoded by this organism. This information will be used in conjunction with global gene expression profiles and representative models of catheter biofilm formation, to identify efflux systems involved in biofilm formation.
Mutants lacking efflux systems up-regulated during biofilm formation will be constructed and characterised, to understand their role in biofilm formation and other traits relevant to infection. This will include ability to form crystalline biofilms in models of infection, changes in antimicrobial susceptibility, cell-cell communication, and virulence using the wax moth larvae model.
To understand if efflux systems modulate wider gene networks governing biofilm formation, global gene expression profiles will be obtained from defined efflux mutants, as well as cells subjected to non-specific chemical inhibition of efflux. The role of additional genes associated with efflux and biofilm formation will also be explored through mutagenesis and modelling. In collaboration with Dr KM Rahman at Kings College London, we will explore the interaction of target efflux systems with potential inhibitors using in silico modelling approaches and biological assays.
Applicants for a studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an area appropriate to the skills requirements of the project.
IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form: https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-doctoral-training-partnership-student-appl
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 form the DTP will be required to submit an application to study at Bath.
More information on the application process may be found here: https://www.gw4biomed.ac.uk/doctoral-students/
APPLICATIONS CLOSE AT 17:00 ON 25 NOVEMBER 2019.