About the Project
Staphylococcus aureus uses host antimicrobial copper as a regulatory signal to alter gene expression to promote colonisation. The proposed project will target this response to identify new antimicrobials to treat serious S. aureus skin infection. MRSA are a cause of severe soft skin tissue infections that pose a major economic and clinical burden. The aim of this interdisciplinary project is to build on our expertise of S. aureus copper resistance, novel skin infection models and innovative imaging and mass spectrometry analysis to test our hypothesis that copper resistance plays an important role in S. aureus skin infections and identify novel antimicrobials.
The objectives are to:
1. Characterise the distribution of metal and bacteria, and phagocyte responses in skin infection models.
2. Determine whether copper resistance alters progression to chronic infections in skin infection models.
3. Map metabolites in skin infection models to identify the metabolic status of the host and pathogen.
4. Identify novel S. aureus antimicrobials by screening the 80k compound library.
The student will benefit from expertise spanning three universities: training in microbiology, highly innovative skin infection models, and imaging approaches including super resolution fluorescent and scanning electron microscopy, mass spectrometry and high throughput phenotyping to identify novel antimicrobials.
The student will benefit from a team of supervisors all with the relevant expertise to ensure the success of the project, Professor Julie Morrissey, University of Leicester, Professor Kim Hardie and Dr Rian Griffiths. University of Nottingham, Professor Joan Geogehegan, University of Birmingham, and who have strong links with clinicians and industry.
The MRC Advanced Interdisciplinary Models (AIM) Doctoral Training Partnership (DTP) is a multi-institutional DTP between the Universities of Birmingham, Leicester and Nottingham. You will be based at the institution of the first supervisor. More information about the DTP is here: https://more.bham.ac.uk/mrc-aim/phd-opportunities/
How to apply
Information about how to apply is provided here:
https://more.bham.ac.uk/mrc-aim/phd-opportunities/
All candidates are encouraged to contact the supervisors for an informal discussion before application.
Contact for enquiries
Prof Julie Morrissey ([Email Address Removed])
https://more.bham.ac.uk/mrc-aim/phd-opportunities/
References
References
1. Purves J, Thomas J, Riboldi GP, Zapotoczna M, Tarrant E, Andrew PW, Londoño A, Planet PJ, Geoghegan JA, Waldron KJ, Morrissey JA. A horizontally gene transferred copper resistance locus confers hyper-resistance to antibacterial copper toxicity and enables survival of community acquired methicillin resistant Staphylococcus aureus USA300 in macrophages. (2018) Environ Microbiol. doi: 10.1111/1462-2920.14088.
2. Zapotoczna M., Pelicioli-Riboldi G., Moustafa AM, Dickson E., Narechania A., Morrissey J A., Planet PJ., Holden MTG., Waldron KJ., Geoghegan JA. Mobile genetic element-encoded hypertolerance to copper protects Staphylococcus aureus from killing by host phagocytes (2018) MBio. 2018 9(5). pii: e00550-18.
3. Towell A, Feuillie C, Vitry P, Da Costa TM, Mathelié-Guinlet M, Kezic S, Fleury OM, McAleer MA, Dufrêne YF, Irvine AD, Geoghegan JA. Staphylococcus aureus binds to the N-terminal region of corneodesmosin to adhere to the stratum corneum in atopic dermatitis. Proc Natl Acad Sci U S A 2021 118(1):e2014444118.
4. Jordana-Lluch, E., Garcia, V., Kingdon, A., Singh, N., Alexander, C., Williams, P., and Hardie, K.R. (2020). Development of a polymicrobial model to examine interactions between commensals and pathogens on skin. Frontiers in Microbiology 11:291. doi: 10.3389/fmicb.2020.00291.
5. Zhang, J., Brown, J., Scurr, D., Bullen, A., McLellan-Gibson, K., Williams, P., Alexander, M.R., Hardie, K.R., Gilmore, I.S., and P. D. Rakowska, P.D. (2020) Label-free 3D molecular imaging of a P. aeruginosa biofilm using cryo-OrbiSIMS. Analytical Chemistry 92:9008 https://doi.org/10.1021/acs.analchem.0c01125.
6. Singh, N., Romero, M., Travanut, A., Monteiro, P., Jordana-Lluch, E., Hardie, K.R., Williams, P., Alexander M., and Cameron Alexander, C. (2019) Dual bioresponsive antibiotic and Quorum Sensing inhibitor combination nanoparticles for treatment of Pseudomonas aeruginosa biofilms in vitro and ex vivo. Biomaterials Science. DOI: 10.1039/c9bm00773c
7. Hollmann, B., Perkins, M., Chauhan, V.M, Aylott, J.W., and Hardie, K.R. (2021) Fluorescent nanosensors reveal dynamic pH gradients during biofilm formation. NPJ Biofilms and Microbiomes. 7, 50 (2021). https://doi.org/10.1038/s41522-021-00221-8
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