Last Date: Friday, December 13, 2024
Supervisors: Dr Charles Winterhalter, Prof A Darby, Dr Katarzyna Mickiewicz
Competition Funded PhD Project (Students Worldwide)
Newcastle University MRC DiMeN Doctoral Training Partnership
About the Project:
Bacterial pathogens can survive antibiotic treatment and contribute to the global health threat of antimicrobial resistance. Staphylococcus aureus is the leading Gram-positive bacterium causing death from bacterial infections worldwide (>1 million deaths/year) but despite decades of research, its survival within immune cells and resistance to antibiotic-mediated killing are poorly understood. While antibiotic exposure and immune response are known to promote outbursts of reactive oxygen species leading to DNA damage and impaired bacterial proliferation, the exact mechanisms underpinning these processes are unclear. This stems from the redundancy of DNA repair pathways within the cell, which makes the identification of factors involved in a particular repair pathway extremely challenging, and from the lack of appropriate methods to investigate specific DNA damage repair events. To overcome these issues, the Winterhalter lab recently established an innovative approach to introduce targeted DNA damage and identified several novel genes important for DNA break repair. Critically, inactivating these factors can sensitise clinical strains of S. aureus to very low levels of DNA damage, suggesting strong potential to attenuate the impact of bacterial infections.
This PhD project aims to exploit the DNA damage response to discover the fundamental processes underpinning bacterial death or survival during infection. Using laboratory and clinical strains of S. aureus, you will start by characterising the impact of abnormal damage repair activity in lab growth conditions. To achieve this, you will use genetics to build bespoke strains and carry out fluorescence microscopy investigations to identify degenerated cellular processes (with unrestricted access to high-end microscopes available at the Centre for Bacterial Cell Biology: Winterhalter lab). Next, you will employ next-generation sequencing approaches to characterise the impact of abnormal DNA repair processes on chromosome integrity and genomic maintenance (in-house facilities hosted by the Winterhalter/Darby labs). Finally, you will combine and apply these techniques in the context of infection using immune cells such as macrophages and neutrophils (facilities hosted by the Winterhalter/Mickiewicz labs). Together, this project will equip you a highly sought-after skillset in microbiology including fundamental and infection science, and your work will have significant potential to shift the current understanding of antimicrobial resistance. Ultimately, your efforts may contribute to paving the way towards the development of alternative and more efficient antibiotic treatments.
Useful links:
– Primary supervisor (Winterhalter lab, Newcastle): https://www.ncl.ac.uk/medical-sciences/people/profile/charleswinterhalter.html, Twitter/X @Ch_Winterhalter
– Secondary supervisor (Darby lab, Liverpool): https://www.liverpool.ac.uk/people/alistair-darby, Twitter/X @acdarby
– Tertiary supervisor (Mickiewicz lab, Newcastle): https://www.ncl.ac.uk/medical-sciences/people/profile/katarzynamickiewicz.html, Twitter/X @MicKasia
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, 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, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website:
Funding Notes:
Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend (£19,237 for 2024/25) 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: View Website
Studentships commence: 1st October 2025
Good luck!
References
Please note that the Winterhalter lab (primary supervisor) is currently preparing a research article to publish the results and method leading up to this project. An open-access link will be released upon submission for peer-review.
Other references include:
(1) SirA inhibits the essential DnaA:DnaD interaction to block helicase recruitment during Bacillus subtilis sporulation, Nucleic Acids Research (2023) 51:4302 (co-authored by two PhD students). https://pubmed.ncbi.nlm.nih.gov/36416272/
(2) The DNA replication initiation protein DnaD recognises a specific strand of the Bacillus subtilis chromosome origin, Nucleic Acids Research (2023) 51:4322 (co-authored by two PhD students). https://pubmed.ncbi.nlm.nih.gov/37093985/
(3) The bacterial replication origin BUS promotes nucleobase capture, Nature Communications (2023) 14:8339 (co-authored by two PhD students including co-first author). https://pubmed.ncbi.nlm.nih.gov/38097584/
(4) Stepwise evolution of Salmonella Typhimurium ST313 causing bloodstream infection in Africa, Nature Microbiology (2021) 6:327 (co-authored by three PhD students including first author). https://pubmed.ncbi.nlm.nih.gov/33349664/
(5) Intermittent Lactobacilli-containing Vaginal Probiotic or Metronidazole Use to Prevent Bacterial Vaginosis Recurrence: A Pilot Study Incorporating Microscopy and Sequencing, Scientific Reports (2020) 10:3884. https://pubmed.ncbi.nlm.nih.gov/32127550/
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