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MRC DiMeN Doctoral Training Partnership: A molecular understanding of the outer membrane protein assembly pathway in gram negative bacteria to underpin the discovery of new antibiotic targets


MRC DiMeN Doctoral Training Partnership

Leeds United Kingdom Analytical Chemistry Biochemistry Bioinformatics Biophysics Microbiology Molecular Biology Structural Biology

About the Project

Gram negative bacteria comprise 9 of the 12 bacteria that pose the greatest threat to human health, as identified by the World-Health Organisation. New therapeutic strategies are urgently needed to target gram negative bacteria to counter the threat of these pathogens to human health, especially those pathogens that are multi-drug resistant.

All gram negative bacteria have an outer membrane (OM) that is packed with OM proteins (OMPs) that are vital for bacterial survival. A complex assembly line has evolved to shuttle OMPs from their site of synthesis in the cytoplasm to the OM. This assembly line comprises chaperones in the periplasm (Skp and SurA) that escort OMPs to the OM, and the membrane-embedded BAM (beta-barrel assembly machinery), which inserts them into the OM. Efficient OMP synthesis is essential for bacterial viability, and therefore targeting this pathway with new drug-like molecules is an emerging strategy to treat infections by gram negative pathogens. However, the molecular details of this pathway, and how all the components of the assembly line function together remains poorly understood, hampering drug discovery efforts.

In this project, you will receive training in state-of-the-art proteomics and structural mass spectrometry methods and use these tools, combined with a suite of biochemical and bacterial growth assays to understand the molecular details of how the OMP biogenesis pathway coordinates OMP assembly. These approaches will also be used to reveal the molecular mechanism by which drug-like molecules target this process. This will aid in the design of much-needed new antibiotics against gram negative bacteria that cause disease to humans, plants and animals.

You will be based in the laboratories of Dr Antonio Calabrese (https://www.calabreselab.com/, https://twitter.com/anton_calabrese) and Prof Sheena Radford (http://sheena-radford-lab.uk/, https://twitter.com/RadfordLab), and join a team of researchers working to uncover the molecular mechanism of OMP biogenesis.

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 and how to apply can be found on our website:
https://bit.ly/3lQXR8A

Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website

Studentships commence: 1st October 2021

Good luck!

References

A. N. Calabrese, B. Schiffrin, M. Watson, T. K. Karamanos, M. Walko, J. R. Humes, J. E. Horne, P. White, A. J. Wilson, A. C. Kalli, R. Tuma, A. E. Ashcroft, D. J. Brockwell, S. E. Radford. Inter-domain dynamics in the chaperone SurA and multi-site binding to its outer membrane protein clients. Nat Commun 11, 2155 (2020).

B. Schiffrin, A. N. Calabrese, P. W. A. Devine, S. A. Harris, A. E. Ashcroft, D. J. Brockwell, S. E. Radford, Skp is a multivalent chaperone of outer-membrane proteins. Nat Struct Mol Biol 23, 786–793 (2016).

J. E. Horne, M. Walko, A. N. Calabrese, M. A. Levenstein, D. J. Brockwell, N. Kapur, A. J. Wilson, S. E. Radford, Rapid Mapping of Protein Interactions Using Tag‐Transfer Photocrosslinkers, Angew. Chem. Int. Ed., 57, 16688 (2018).

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