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MRC DiMeN Doctoral Training Partnership: Towards phage therapy: combining genetics and cutting edge CryoEM to optimise a superbug-killing virus


   MRC DiMeN Doctoral Training Partnership

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  Dr R Fagan  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Increasing resistance to antibiotics is one of the greatest health challenges facing humanity today. Clostridioides difficile is the primary cause of antibiotic-associated infections in UK hospitals and antibiotic-induced disruption of the gut microbiota is a prerequisite for infection. Current treatments rely on a small number of antibiotics but these cause further damage to the microbiota and relapse is common. There is an urgent need for species specific therapeutics that can kill C. difficile while sparing the beneficial species of the gut microbiota. Bacteriophage are a promising solution to this tricky problem.

Phage are efficient and specific killers of C. difficile and could be further refined through guided genetic engineering. We have developed a streamlined CryoEM pipeline for the structural and mechanistic analysis of phage and have already solved the near atomic resolution structures of two complete contractile phages and one phage tail-like particle that kill C. difficile. We have also shown that the S-layer is the major receptor for the majority of C. difficile phage (1, 2) and have solved the structure of this cell surface structure (3).

In this project we aim to use the insights gained from structural analysis to engineer a phage to efficiently kill clinically important lineages of C. difficile. Our focus will be on answering three key questions:

1.    What is the optimum phage tail length and contraction ratio for effective envelope penetration?

2.    Can we engineer phage with wider specificity using hybrid receptor binding proteins (RBPs)?

3.    What structural changes occur during penetration of the host cell envelope?

It is the exquisite and intricate structural arrangement of components in the phage nanomachine that makes it such an effective killer. We will develop one of our existing well-characterised phage as a test-bed for engineering a better killer. Through an iterative process of genetic modification and CryoEM we will understand the structural features that contribute to bacterial receptor recognition and penetration of the cell envelope during infection. We will also use cutting edge cryo-electron tomography to image phage during infection and determine how our engineered phages differ in modes of infection.

You will receive training at the interdisciplinary interface between molecular microbiology and cryo-electron microscopy, supported by two dynamic research groups with a long-established and successful history of collaboration. Our groups have collaborated closely for 10 years, with three jointly supervised PhD students and two joint postdoctoral scientists.

Supervisors:

Dr Robert Fagan

https://www.sheffield.ac.uk/biosciences/people/academic-staff/robert-fagan

Prof Per Bullough

https://www.sheffield.ac.uk/biosciences/people/academic-staff/bullough

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/how-to-apply


Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: https://www.dimen.org.uk/eligibility-criteria
Studentships commence: 1st October 2023
Good luck!

References

1. Kirk JA, Gebhart G, Buckley AM, Lok S, Scholl D, Douce GR, Govoni GR, Fagan RP (2017) New class of precision antimicrobials redefines role of Clostridium difficile S-layer in virulence and viability. Science Translational Medicine 9:eaah6813
https://pubmed.ncbi.nlm.nih.gov/28878013/
2. Royer ALM, Umansky AA, Allen MM, Garneau JR, Ospina-Bedoya M, Kirk JA, Govoni GR, Fagan RP, Soutourina O, Fortier LC (2022) The Clostridioides difficile S-layer protein A (SlpA) serves as a general phage receptor. bioRxiv 10.1101/2022.09.19.508581
https://www.biorxiv.org/content/10.1101/2022.09.19.508581v1
3. Lanzoni-Mangutchi, P., Banerji, O., Wilson, J., Barwinska-Sendra, A., Kirk J.A., Vaz, F., O’Beirne, S., Basle, A., El Omari, K., Wagner, A., Fairweather, N.F., Douce, G.R., Bullough, P.A.*, Fagan, R.P.*, Salgado, P.S.* (2022) Structure and assembly of the S-layer determine virulence in C. difficile. Nature Communications 13:970
https://www.nature.com/articles/s41467-022-28196-w
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