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MRC DiMeN Doctoral Training Partnership: Addressing antimicrobial resistance (AMR): Affimers as therapeutic candidates and tools in antibacterial drug discovery

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  • Full or part time
    Dr A O'Neill
    Dr D Tomlinson
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

The World Health Organization (WHO) has declared antimicrobial drug resistance (AMR) one of the greatest threats to human health, and it is predicted that this phenomenon will kill 10 million people annually by 2050 if not addressed. New drugs – particularly those active against bacteria - are urgently needed to replace antibiotics whose activity has become eroded by resistance. Based on promising preliminary findings, this project intends to exploit Affimer (artificial antibody) technology developed at Leeds as a cutting-edge solution to this problem.

Affimers isolated to bind/ inhibit bacterial proteins will be employed in two ways. Firstly, Affimers that we have already raised against specific surface proteins on pathogenic bacteria and inhibit growth will be optimised to further increase potency, with the aim of directly generating therapeutic candidates. A range of biophysical and structural biology approaches will be employed to characterize optimised Affimers and their interaction with target proteins. Antibodies exerting a direct antibacterial action have not to date been developed for clinical use; our discovery that Affimers can be selected that are capable of blocking bacterial growth makes such an approach feasible for the first time.

Second, expression of Affimers inside bacteria will be used to define new targets for therapeutic intervention that it has not been possible to validate through existing means (e.g. virulence factors). Existing approaches to validate novel antibacterial drug targets usually employ genetic inactivation, and are inadequate to assess if inhibition of the target is capable of resolving an infection that is already underway. By contrast, Affimers will allow rapid and direct knock-down of target function in a model of established infection, thereby conclusively determining whether a target has therapeutic potential. Collectively, these studies will establish Affimers as a platform technology to underpin future antibacterial drug discovery efforts.

This project represents a collaboration with Public Health England (PHE) at Porton Down, and the student will undertake a placement of several months’ duration at PHE during the course of the PhD to evaluate the performance of Affimers in an insect model of infection (Galleria mellonella). This is therefore a truly interdisciplinary study, lying at the interface between biotechnology, drug discovery and translational medicine, and as such, will deliver the appointed student with training in skills relevant to all three cross-cutting themes that the MRC currently lists as priorities (interdisciplinary skills, quantitative skills, and whole organism physiology).

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

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 2019.

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

Nass, N. M. et al. (2017) Revisiting unexploited antibiotics in search of new antibacterial
drug candidates: the case of γ-actinorhodin. Sci Rep. 7(1):17419. doi: 10.1038/s41598-017-17232-1.

Tiede, C. et al. (2017) Affimer proteins are versatile and renewable affinity reagents. Elife.6. pii: e24903. doi: 10.7554/eLife.24903.



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