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Combating Clostridium difficile infection through spore germination control

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  • Full or part time
    Prof N Minton
    Dr Ruth Griffin
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Clostridium difficile is the major cause of healthcare associated gastrointestinal infections in acute care hospitals across Europe and the USA. Its principle mode of transmission is through its highly resistant spores. In recent years it has emerged that the main germinant of C. difficile spores in the GI tract are primary bile acids. During their intestinal transit, bile acids undergo transformations into secondary bile acids due to the action of intestinal microbes. Secondary bile acids inhibit spore germination. Accordingly, the concept has emerged that it is the elimination of those bacteria from the microbiome that undertake bile acid conversion, through the administration of antibiotics, that leads to the emergence of C. difficile infections through the promotion of spore germination.

The aim of this PhD project is to exploit the progress made within Nottingham’s BBSRC/EPSRC Synthetic Biology Research Centre (SBRC) in the development of advanced clostridial gene tools to better understand how the microbiome controls C. difficile. We are particularly interested in those group of microbes that convert primary bile acids to secondary bile and the metabolic pathways involved. This will involve the derivation and optimisation of gene transfer procedures, the inactivation and modification of bile pathway genes/ enzymes using CRISPR/Cas9, the use of random transposon tools for pathway characterisation and the use of orthogonal expression systems to control pathway performance.

The 3-year PhD project is jointly funded by the US company ATUM and the University of Nottingham. The project will be aligned to a collaborative project involving the Universities of Berne, Lausanne and Zurich funded by the Swiss National Funding Council and to the NIHR BioMedical Research Centre hosted by the Nottingham University Hospitals NHS Trust. You will be based the £14.3M BBSRC/EPSRC Synthetic Biology Research Centre (SBRC – www.sbrc-nottingham.ac.uk), one of only six such centres in the UK, and occupy state-of-the-art facilities within Nottingham’s flagship science building, the Centre for Biomolecular Sciences. With a £1.1M Beckman Robotic workstation and 11 twin occupancy anaerobic cabinets, they are one of the best equipped laboratories for anaerobe studies in the UK.

Please send applications to: [Email Address Removed]

The University of Nottingham is one of the world’s most respected research-intensive universities, ranked 8th in the UK for research power (REF 2014). Students studying in the School of Life Sciences will have the opportunity to thrive in a vibrant, multidisciplinary environment, with expert supervision from leaders in their field, state-of-the-art facilities and strong links with industry. Students are closely monitored in terms of their personal and professional progression throughout their study period and are assigned academic mentors in addition to their supervisory team. The School provides structured training as a fundamental part of postgraduate personal development and our training programme enables students to develop skills across the four domains of the Vitae Researcher Development Framework (RDF). During their studies, students will also have the opportunity to attend and present at conferences around the world. The School puts strong emphasis on the promotion of postgraduate research with a 2-day annual PhD research symposium attended by all students, plus academic staff and invited speakers.

Funding Notes

The 3-year PhD project is jointly funded by the US company ATUM and the University of Nottingham. The project will be aligned to a collaborative project involving the Universities of Berne, Lausanne and Zurich funded by the Swiss National Funding Council and to the NIHR BioMedical Research Centre hosted by the Nottingham University Hospitals NHS Trust.

References

Cañadas IC, Groothuis D, Zygouropoulou M, Rodrigues R, Minton NP. RiboCas: A Universal CRISPR-Based Editing Tool for Clostridium. ACS Synth Biol. 2019; 8(6): 1379-1390.

Woods C, Humphreys CM, Rodrigues RM, Ingle P, Rowe P, Henstra AM, Köpke M, Simpson SD, Winzer K, Minton NP. A Novel Conjugal Donor Strain for Improved DNA transfer into Clostridium spp. Anaerobe. 2019 Jun 30. pii: S1075-9964(19)30117-9.

Ingle P, Groothuis D, Rowe P, Huang H, Cockayne A, Kuehne SA, Jiang W, Gu Y, Humphreys CM, Minton NP. Generation of a fully erythromycin-sensitive strain of Clostridioides difficile using a novel CRISPR-Cas9 genome editing system. Sci Rep. 2019; 9(1): 8123.

Studer N, Desharnais L, Beutler M, Brugiroux S, Terrazos MA, Menin L, Schürch CM, McCoy KD, Kuehne SA, Minton NP, Stecher B, Bernier-Latmani R, Hapfelmeier S. Functional Intestinal Bile Acid 7α-Dehydroxylation by Clostridium scindens Associated with Protection from Clostridium difficile Infection in a Gnotobiotic Mouse Model. Front Cell Infect Microbiol. 2016; 6: 191

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FTE Category A staff submitted: 90.86

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