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PhD Studentship: The role of efflux systems in antimicrobial susceptibility and virulence of the urinary tract pathogen Proteus mirabilis

University of Bath - Biology & Biochemistry

Qualification Type: PhD
Location: Bath
Funding for: UK Students, EU Students
Funding amount: £14,777 annual stipend (2018/19 rate) + tuition fees + £1,000 p/a training support grant for up to 3.5 years
Hours: Full Time
Placed On: 8th November 2018
Closes: 16th December 2018

Lead supervisor:  Dr Brian Jones, Department of Biology & Biochemistry (University of Bath)

Enquiries: b.v.jones@bath.ac.uk

Co-supervisors: Dr Mark Sutton (Public Health England), Dr K Miraz Rahaman (King’s College London)

Efflux systems are molecular “pumps” that remove toxic substances from cells, including antibiotics, and play an important role in antimicrobial resistance (AMR). There is also an emerging role for efflux systems in a range of processes important for bacterial infection, including biofilm formation, cell-cell communication, and survival within infected hosts. Our recent work has shown that efflux is important for biofilm formation and resistance to a broad range of antimicrobials, in the urinary tract pathogen Proteus mirabilis. Inhibition of efflux can reduce biofilm formation by this and other pathogens, and increase susceptibility to commonly used disinfectants and antiseptics, highlighting efflux pumps as viable targets for development of new drugs to control infection. 

This project aims to determine how changes in efflux pump expression affects traits relevant to infection, using P. mirabilis as clinically relevant model organism. P. mirabilis forms extensive crystalline biofilms on urethral catheters that block urine flow, leading to serious clinical complications including septicaemia and endotoxic shock. Our hypothesis is that mutations in efflux regulation which promote AMR also influence traits such as biofilm formation. The project will be a collaboration with Public Health England and Kings College London, providing interdisciplinary training with experts from the National Infections Service and Institute of Pharmaceutical Science. 

Objective 1: 

Clinical isolates will be used in adaptation experiments to identify efflux systems involved in development of AMR. Following serial exposure to increasing concentrations of antimicrobials, mutants with stable reductions in antimicrobial susceptibility will be isolated, and characterised by whole genome sequencing and quantitative PCR, to identify efflux systems and associated regulatory genes with altered expression. 

Objective 2: 

Mutants with altered efflux activity will be further characterised to determine how this affects traits relevant to P. mirabilis pathogenesis, including motility, cell-cell communication, virulence, and biofilm formation. The impact on wider aspects of gene regulation will also be explored through comparison of global transcriptional profiles, between adapted strains with efflux mutations and parental isolates. 

Objective 3: 

A combination of in silico modelling, mutagenesis, biological, and biochemical assays will be used to determine the substrate specificity of target efflux pumps. Molecular modelling will be used to predict the likely substrates of efflux systems, and coupled with fluorescence uptake/efflux assays, direct measurement of metabolites in cells and the cell supernatant (LC MS, HR-MAS), and the use of reporter strains to sense the presence of particular molecules (e.g. quorum sensing/inhibiting, toxic intermediates). 

Candidate:

Applicants should hold, or expect to receive, a First Class or high Upper Second Class UK Honours degree (or the equivalent qualification gained outside the UK) in a relevant subject. A master’s level qualification would also be advantageous. 

Applications:

Formal applications should be made via the University of Bath’s online application form: 
https://samis.bath.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RDUBB-FP02&code2=0013

Please quote the supervisor’s name and project title in the ‘Your research interests’ section. 

For more information about applying see: 
http://www.bath.ac.uk/guides/how-to-apply-for-doctoral-study/ 

Anticipated start date: 30 September 2019.

Funding:

Candidates may be considered for a University Research Studentship covering UK/EU tuition fees, a training support fee of £1,000 p.a. and a tax-free maintenance allowance at the UKRI Doctoral Stipend rate (£14,777 in 2018-19) for a period of up to 3.5 years.

   
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