This project is one of a number that are in competition for funding from the South West Biosciences Doctoral Training Partnership (SWBio DTP). The DTP offers an interdisciplinary research training programme delivered by a consortium comprising the Universities of Bath, Bristol and Exeter, Cardiff University and Rothamsted Research, alongside six regional associate partners: Marine Biological Association, Plymouth Marine Laboratory, Swansea University, UCB Pharma, University of the West of England and SETsquared Bristol. The partnership has a strong track record in advancing knowledge through high quality research and teaching, in collaboration with industry and government. For more information about the DTP, see https://www.swbio.ac.uk/
Studentships are available for entry in September/October 2020.
All SWBio DTP projects will follow a structured 4-year PhD model, combining traditional project-focussed studies with a taught first year which includes directed rotation projects.
Overview of this PhD project:
Dr Susanne Gebhard, Department of Biology & Biochemistry (University of Bath) https://researchportal.bath.ac.uk/en/persons/susanne-gebhard
Prof Jody Mason (University of Bath) https://researchportal.bath.ac.uk/en/persons/jody-mason
Dr Steven Porter (University of Exeter) https://biosciences.exeter.ac.uk/staff/profile/index.php?web_id=steven_porter
Antibiotic resistance is one of the grand challenges faced by modern medicine, and tremendous efforts are invested in developing new treatments to slow its spread. One exciting approach is the development of anti-resistance drugs that do not themselves inhibit bacteria, but instead block resistance and reinstate the usefulness of our existing antibiotics.
Many resistance mechanisms are tightly regulated by the bacteria and only expressed in the presence of antibiotics. Dedicated signalling pathways detect the presence of drugs and transmit this information to the cell’s interior to activate gene expression. If signalling can be blocked, resistance can no longer be activated and the bacterium once again becomes susceptible to the antibiotic. In this PhD project, you will investigate the development and characterisation of peptide-based inhibitors of such a signalling pathway. As a member of the Gebhard lab, you will tap into over 10 years’ experience in signalling pathways that control antibiotic resistance in Gram-positive bacteria. Specifically, you will focus on histidine kinases of the BceS type. These proteins possess a coiled-coil structure at their core, which is known to be essential for their function. In an exciting interdisciplinary collaboration, you will work with the Mason lab, who have pioneered the use of peptide antagonists to disrupt coiled-coil protein function. This has had great success in the context of cancer and neurodegenerative disease and is now ready to be applied to bacterial signalling.
You will begin with in silico analyses of protein and peptide sequences, to define the most promising starting point for inhibitor design. A combination of random and directed peptide screening approaches will identify functional antagonists, which you will take forward for biochemical characterisation. This will be supported by the Porter lab in Exeter, who are experts in bacterial kinase biochemistry. Antibiotic susceptibility and signalling assays will test the ability of your peptide antagonists to block resistance in living cells. Finally, by comparing endogenously produced to externally added peptides, you will begin to explore aspects of drug delivery, such as permeability to reach intracellular targets.
The composition of the supervisory team ensures comprehensive expertise in all facets of this interdisciplinary project. You will find a supportive and stimulating training environment to guide you through the challenges and rewards of this project. The conserved structure of histidine kinases and designability of peptide antagonists means that your results will be translatable to other systems, opening up a new avenue for combating resistance.
Applicants 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 appropriate area of science or technology.
How to apply:
Applications should be submitted on the University of Bath’s online application form for a PhD in Biosciences: https://samis.bath.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RDUBB-DT01&code2=0004
Please ensure that you quote the supervisor’s name and project title in the ‘Your research interests’ section. You may apply for more than one project if you wish but you should submit a separate personal statement relevant to each one.
More information about applying for a PhD at Bath may be found on our website: https://www.bath.ac.uk/guides/how-to-apply-for-doctoral-study/