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 Susanne Gebhard, Department of Biology & Biochemistry
Co-supervisors: Prof Jody Mason (Bath) and Dr Steven Porter (Exeter)
Antibiotic resistance is one of the grand challenges in modern medicine, with tremendous efforts invested in finding new drugs that can kill resistant microbes. This PhD project will explore an exciting alternative approach: the development of anti-resistance drugs that do not directly harm the bacteria but instead reinstate the effectiveness of our existing arsenal of antibiotics.
Resistance mechanisms are often tightly controlled by bacteria and only activated if an antibiotic is present. This occurs via signaling pathways that detect the presence of a drug and relay this information inside the cell. Signaling can therefore be regarded as the first step of resistance. To date, anti-resistance drugs are mostly designed to disrupt the function of the resistance mechanism itself. A novelty in this PhD will be to instead target the signaling pathways and find inhibitors that block activation of resistance in the first place. As the successful student, you will focus on a histidine kinase that controls resistance in many Gram-positive bacteria. Histidine kinases contain a central helical domain with a coiled-coil arrangement, a structure commonly found in proteins. The project’s co-supervisor has pioneered the use of peptide antagonists to disrupt the function of coiled-coil proteins, with great success in the context of cancer and neurodegenerative disease. This PhD project now brings this cutting-edge technology to bacterial signaling in a truly interdisciplinary approach to drug discovery.
Building on extensive expertise in the supervisory team, you will initially use in silico predictions to identify the most promising peptide sequences for kinase inhibition. This will be the starting point for targeted and random screens to find effective peptide inhibitors. The established screening platform for coiled-coil inhibitors is based on a bacterial system already, making this approach highly feasible despite the novelty of the context. Lead peptides will be characterized biochemically and in vivo, to test their ability to block signaling and resistance. Using endogenous peptide production in the bacteria and addition of synthetic peptides will allow you to begin exploring aspects of drug delivery, moving closer to application.
The broad expertise of the supervisory team will ensure cross-cutting training in all practical and theoretical methodology required for the project. International collaborations are in place with a number of companies that specialise in commercialisation of peptides as drugs, including mechanisms to reach intracellular targets.
Histidine kinases are structurally conserved and results will be highly translatable to other resistance systems. At the same time, protein interactions are very specific allowing targeted inhibitor design to maximize selectivity and minimize side effects. The outcomes of this PhD project are therefore expected to open a new perspective on combating resistance.
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.