Stopping a superbug's sleeping cells: molecular machines of sporulation at atomic level


   MRC DiMeN Doctoral Training Partnership

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  Prof P Salgado, Dr J Blaza  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Interested in a PhD studying antibiotic resistant bacteria and explore new ways to treat drug-resistant infections? In this PhD, you will use a range of biochemistry, biophysical and structural techniques, together with molecular biology, genetics, and microbiology approaches to investigate structure and function of essential proteins that can open new therapeutical avenues to fight the superbug C. difficile.

C. difficile is an opportunistic and highly antibiotic-resistant pathogen that relies on disruption of the gut microbiota due to antibiotics to cause disease. Current treatments with second line antibiotics further exacerbate the problem and often lead to recurrent and persistent episodes. We urgently need to develop species-specific antimicrobials that kill C. difficile without impacting the gut microbiota.

The infectious agent of C. difficile is a dormant cell form (spore) that is resistant to physical and chemical agents. Spore formation is a promising but unexploited target for new therapeutics but many functional details, particularly for early stages, are poorly understood. Our work focusses on proteins that we have shown to be essential for spore formation [1,2,3]. Targeting dormant cells, less prone to the evolutionary pressure of antibiotic drugs, will carry a reduced risk of development of new resistance mechanisms by the bacteria. This approach will decrease transmission and environmental contamination, which would be of great societal benefit.

In order to develop these new therapeutical approaches, we need to understand the spore formation machinery at the atomic level. The process of engulfment of the future spore by the mother cell membrane involves several proteins and remodelling of the peptidoglycan [1, 4]. Currently, we have identified two peptidoglycan degrading enzymes (DP) [2] and a putative channel (Q:AH) [3, 4] as part of the “engulfasome” [1]. The main aim is the structural determination of the engulfosome, building from the Q:AH complex and higher order sub-complexes. You will also carry out identification and characterisation of other proteins that interact with DP/Q:AH to provide a complete view of the engulfasome’s composition, structure and function.

The studentship will provide invaluable training in biochemical and biophysical techniques, structural biology as well as molecular biology and microbiology, which will be highly desirable for a future career in research into antimicrobial resistance (AMR). AMR is an increasingly global problem with new therapeutics and approaches urgently needed. You will use state-of-the-art protein crystallisation facilities at Newcastle University and cryo-electron microscopy at the University of York. You will also have access to the UK’s synchrotron and associated facilities at Diamond Light Source.

You will join our multi-disciplinary team between Prof Paula Salgado at Newcastle University and Dr Jamie Blaza at the University of York. You will work alongside other students and postdoctoral scientists studying the biochemistry and biology of C. difficile sporulation at Newcastle University and experts in cryo-EM at the York Structural Biology Laboratory. 

You can find out more about the Salgado Lab and our work or get in touch!

Also on Twitter/X @pssalgado, Mastodon @[Email Address Removed] and BSky @pssalgado.bsky.social

https://salgadolab.org/

https://twitter.com/pssalgado

https://mastodon.social/@paulasalgado

https://bsky.app/profile/pssalgado.bsky.social

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

Biological Sciences (4)

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend (£18,622 p.a. for 2023/24)) 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 2024
Good luck!

References


1. Kelly, A., Salgado, P.S.# (2019) The engulfasome in C. difficile: Variations on protein machineries. Anaerobe 60, 102091 https://doi.org/10.1016/j.anaerobe.2019.102091
2. Dembek, M., Kelly, A., Barwinska‐Sendra, A., Tarrant, E., Stanley, W. A., Vollmer, D., Biboy, J., Gray, J., Vollmer, W. and Salgado, P.S.# (2018) Peptidoglycan degradation machinery in Clostridium difficile forespore engulfment. Mol Micro, 110: 390-410 https://doi.org/10.1111/mmi.14091
3. Serrano, M., Crawshaw, A.D.*, Dembek, M.*, Monteiro, J., Pereira, F., Gomes de Pinho, M., Fairweather, N.F., Salgado, P.S.#, Henriques, A.O.# (2016) The SpoIIQ-SpoIIIAH complex of Clostridium difficile controls forespore engulfment and late stages of gene expression and spore morphogenesis. Mol Micro 100: 204–228 https://doi.org/10.1111/mmi.13311
4. Crawshaw, A.D., Serrano, M., Stanley, W.A., Henriques, A.O., Salgado, P.S.# (2014) A mother cell-to-forespore channel: current understanding and future challenges. FEMS Microbiology Letters, 358: 129–136 https://doi.org/10.1111/1574-6968.12554
5. Dembek, M., Willing, S.E., Hong, H.A., Hosseini, S., Salgado, P.S.#, Cutting, S.M..# (2017) Inducible expression of Spo0A as a tool for increasing sporulation efficiency in Clostridium difficile. Frontiers in Microbiology, 1793 https://doi.org/10.3389/fmicb.2017.01793
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