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

  • Full or part time
  • Application Deadline
    Sunday, December 16, 2018
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

SUPERVISORY TEAM

Lead supervisor: Dr Brian Jones, Department of Biology & Biochemistry, University of Bath
Co-supervisors: Dr Mark Sutton (Public Health England), Dr K Miraz Rahaman (King’s College London)

BACKGROUND

Efflux systems are molecular “pumps” that remove toxic substances from cells, including antibiotics, and play an important role in antimicrobial resistance (AMR). However, 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.

AIMS AND OBJECTIVES

The aim of this project is 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).

TRAINING

The project will provide cross-disciplinary training in a wide range of cutting edge techniques, but will also offer a firm grounding in conventional microbiological assays and experimental design. The successful student will join an established multidisciplinary network of postgraduate students, postdoctoral researchers and PIs across three leading research institutions, which collectively provide all essential facilities.

Bath have established novel infection models, biochemical assays, and molecular genetic tools for manipulation of P. mirabilis and evaluation of biofilms, as well and sequencing facilities. This will underpin genomic, transcriptomic, and phenotypic aspects of the work. Bath run a range of relevant training courses, including R statistics, bioinformatics, and coding, and is part of the MRC CLIMB Bioinformatics infrastructure consortium (http://www.climb.ac.uk) which provides computational resources and support for sequence analysis.

The student will also access further expertise, training, and equipment through working with PHE and the Institute of Pharmaceutical Sciences. Work at PHE (supervised by Dr Sutton) will provide experience of a non-academic research environment as well as access to transcriptome workflows for biofilm analyses, and novel assays for understanding efflux activity in bacteria. Work at Kings (Supervised by Dr Rahman) will provide experience in medicinal chemistry and chemoinformatic techniques.

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

More information about applying for a PhD at Bath may be found here:
http://www.bath.ac.uk/guides/how-to-apply-for-doctoral-study/

Anticipated start date: 30 September 2019.

Funding Notes

Candidates may be considered for a University Research Studentship which will cover UK/EU tuition fees, a training support fee of £1,000 per annum 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.

References

• Jamshidi et al. (2018) Mapping the Dynamic Functions and Structural Features of AcrB Efflux Pump Transporter Using Accelerated Molecular Dynamics Simulations. Scientific Reports 8:10470.

• Nzakizwanayo et al. (2017) Fluoxetine and thioridazine inhibit efflux and attenuate crystalline biofilm formation by Proteus mirabilis. Scientific Reports 7:12222.

• Picconi et al. (2017) Triaryl benzimidazoles as a new class of antibacterial agents against resistant pathogenic microorganisms. J Med Chem. 60:6045

• Holling et al. (2014). Elucidating the genetic basis of crystalline biofilm formation in Proteus mirabilis. Infect Immun, 82: 1616.

How good is research at University of Bath in Biological Sciences?

FTE Category A staff submitted: 24.50

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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