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MRC DiMeN Doctoral Training Partnership: How to kill a difficult superbug: understanding the evolution of antimicrobial resistance in Clostridioides difficile

  • Full or part time
    Dr R Fagan
  • Application Deadline
    Monday, January 06, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

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. Vancomycin is the treatment of choice for severe or recurrent infection but this causes further damage to the microbiota and relapse is common. Worryingly, vancomycin resistance is now common in many bacterial species and reports are emerging of increasing resistance in C. difficile. Our industrial partners Summit Therapeutics are developing an innovative new narrow spectrum antibiotic ridinilazole (RDZ), to treat C. difficile infection and prevent its recurrence by preserving the gut microbiota. In a Phase 2 clinical trial RDZ proved to be more effective than vancomycin and showed ~ 60% reducution in rate of recurrence. RDZ is currently in Phase 3.

In this project we will analyse the evolution of resistance to the current frontline antibiotic vancomycin and the promising new therapeutic RDZ, answering two key questions:

1) How does resistance evolve and what are the molecular mechanisms?
2) What are the fitness costs of developing resistance to these antibiotics?

In this project, supported by the Fagan (www.sheffield.ac.uk/mbb/staff/robertfagan) and Brockhurst (www.sheffield.ac.uk/aps/staff-and-students/acadstaff/brockhurst) groups, along with our industrial partners Summit Therapeutics (www.summitplc.com), you will be trained in evolutionary biology and microbiology. You will experimentally evolve resistance to vancomycin and RDZ and use whole genome sequencing and cutting-edge molecular microbiology techniques to identify and confirm the responsible mutations. Resistance often comes at a cost so you will use classical microbiology approaches to monitor fitness as resistance emerges and bacterial genetics, biochemistry and advanced microscopy to understand the molecular basis. These experiments will reveal the mechanisms of resistance to vancomycin and RDZ that will eventually emerge in the clinic. This will allow direct comparison of the evolutionary risks of resistance emergence against the current frontline antibiotic and a promising future therapeutic.

You will receive training at the interdisciplinary interface between molecular microbiology and evolutionary biology, supported by two dynamic research groups based within the wider Florey Institute (www.floreyinstitute.com/) that applies fundamental molecular biology to address clinical antibiotic resistance. During your PhD you will also have the opportunity to have a 3 month placement with Summit Therapeutics, experiencing what it’s like to work with a biotech company at the forefront of antibiotic research and development.


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 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: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

iCASE Award: Industrial partnership project:

Fully funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner. Enhanced stipend, tuition fees and budget for consumables, travel and subsistence.

Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

References

Vickers RJ, Tillotson GS, Nathan R, Hazan S, Pullman J, Lucasti C, Deck K, Yacyshyn B, Maliakkal B, Pesant Y, MD,Tejura B, Roblin D, Gerding DN, Wilcox MH (2017) Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Lancet Infectious Diseases. 17(7): 735–744.

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

Bottery MJ, Wood AJ & Brockhurst MA (2017) Adaptive modulation of antibiotic resistance through intragenomic coevolution. Nature Ecology and Evolution
1:1364

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