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MRC DiMeN Doctoral Training Partnership: To kill and cure: Understanding antibiotic action to enhance activity


MRC DiMeN Doctoral Training Partnership

Sheffield United Kingdom Biochemistry Biophysics Genetics Medical Physics Microbiology Molecular Biology

About the Project

Antibiotics are at the core of modern medicine, but they are under threat due to the spread of resistance.  Antibiotics either kill (bactericidal) or stop bacteria growing (bacteriostatic).  Extraordinarily we still do not know why only some antibiotics kill or what mechanism(s) lead to death.  Such understanding will underpin the rational use of existing and aid in the design of novel interventions to reduce the burden of disease.  Our recent research has begun to elucidate the principles underpinning bacterial growth and division (Nature, 2020), how these are compromised by antibiotics and how resistance circumvents this action (PLoS Pathogens, 2020).  This has led to a new hypothesis whereby bactericidal antibiotics, such as penicillin, kill due to a dysregulation of cell wall homeostasis, in the absence of synthesis.  The aim of the project is to take an interdisciplinary approach to unravel the fundamental mechanisms governing how antibiotics kill bacteria.

Objectives:

1.    To evaluate the ability of different antibiotics to lead to bacteriostasis or death.

2.    Determine the molecular events leading to bacterial cell death.

3.    Develop rational drug combinations to test the mechanisms leading to cell death and to explore how these might be exploited. 

 

Experimental Approach:

We have established an integrated, interdisciplinary network of analytical approaches to be able to determine the effect of antibiotics and how they kill cells.  In particular we have a world-leading capability in advanced microscopy approaches to be able to establish bacterial architectural changes in response to antibiotics.  Initially a range of antibiotics, with different targets, will be evaluated for their ability to kill bacteria and then analysed to determine if there is a common mechanism leading to death.  We have found that cell wall antibiotics kill through the appearance of small holes, that penetrate the entire depth of the cell wall leading to loss of integrity, only observable using our microscopy approaches. Establishing the bactericidal mechanisms of antibiotics will allow their combined use to lead to a more rapid and efficient removal of bacteria.  These combinations can then be evaluated using our in vivo capability.

Further information on the research group can be found at:

https://www.sheffield.ac.uk/biosciences/people/mbb-staff/academic/simon-foster

https://thefosterlab.sites.sheffield.ac.uk

And catch us on twitter! @foster_lab

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

• Panchal, V.V., Griffiths, C., Mosaei, H., Bilyk, B., Sutton, J.A.F., Carnell, O.T., Hornby, D.P., Green, J., Hobbs, J.K., Kelley, W.L., Zenkin, N., Foster, S.J. (2020) Evolving MRSA: High-level β-lactam resistance in Staphylococcus aureus is associated with RNA Polymerase alterations and fine tuning of gene expression. PLoS Pathogens 16, e1008672. doi: 10.1371/journal.ppat.1008672.
• Pasquina-Lemonche, L., Burns, J., Turner, R.D., Kumar, S., Tank, R., Mullin, N., Wilson, J.S., Chakrabarti, B., Bullough, P.A., Foster, S.J., Hobbs, J.K. (2020) The architecture of the Gram-positive bacterial cell wall. Nature 582, 294-297. doi: 10.1038/s41586-020-2236-6.
• Lund, V.A., Wacnik, K., Turner, R.D., Cotterell, B.E., Walther, C.G., Grein, F., Wollman, A.J.M., Leake, M.C., Olivier, N., Cadby, A., Mesnage, S., Jones, S., Foster S.J. (2018) Molecular coordination of Staphylococcus aureus cell division. eLife doi: 10.7554/eLife.32057

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