Overview
Antimicrobial resistance (AMR) is a public health crisis driven in large part by plasmids: genetic elements that can transfer multi-drug resistance (MDR) between pathogens. Increasingly, it’s appreciated that plasmids don’t just passively transfer genes, but can actively manipulate cell behaviour, creating bacterial “zombies” with phenotypes better adapted for spreading the plasmid (10.1098/rstb.2020.0461; 10.1371/journal.pbio.3001988). There is an urgent need to understand this overlooked, ‘manipulative’ side to plasmids and how it might accelerate the emergence of antibiotic resistant opportunistic pathogens.
About this opportunity
Pseudomonas aeruginosa, a globally significant, “priority” pathogen (World Health Organisation) often found in nosocomial settings, engages in multifarious interactions with related strains and species which could be manipulated by a plasmid to enhance its own spread. In this project, you will examine how MDR plasmids affect Pseudomonas behaviour. Several families of Pseudomonas plasmids, including a large group of MDR plasmids, harbour chemotaxis regulators, operons for surface-based motility, and genes that rewire processes of cell interactions (10.1038/s41467-020-15081-7, 10.1111/1462-2920.12901, 10.1371/journal.pbio.3001988). The project will therefore focus on two key phenotypes likely to drive plasmid dissemination: motility, and interactions with potential plasmid recipients. You will learn to use cutting-edge automated microscopy together with AI-driven, massively parallel cell-tracking to analyse Pseudomonas motility and behaviour (10.1038/s41564-024-01729-3; 10.1038/s41467-022-35311-4) to deepen our understanding of how plasmids drive AMR.
Objectives:
- How frequently do MDR plasmids harbour operons for rewiring cell movement, and how do such genes evolve? You’ll use bioinformatic approaches to screen databases for motility-related genes, explore operon structure, association/anti-association, and molecular evolution.
- How does MDR plasmid acquisition alter Pseudomonas motility? Do plasmids drive cells towards chemicals produced by potential plasmid recipients? You’ll study fluorescently-labelled strains and plasmids using microfluidic devices/microscopy, and then use cell-tracking to follow and analyse thousands of cell trajectories to compare the fates of individual cells.
- How does MDR plasmid carriage affect Pseudomonas inter-species and inter-strain interactions, particularly within the hospital sink drain microbiome? You’ll use isolates from polymicrobial hospital sink drain biofilm cultures to investigate how plasmid carriage impacts interspecies interactions.
Together, the outputs from these objectives will help us to understand plasmids as elements capable of driving multifaceted behavioural changes in bacteria, beyond simple vectors of resistance elements.
Lab and context:
This project represents a new interdisciplinary collaboration, combining distinct approaches and expertise across the two labs of the supervisory team: evolutionary microbiology (Jamie Hall, Department of Evolution, Ecology and Behaviour; http://www.jpjhall.net) and biophysics (Jamie Wheeler, Department of Clinical Infection, Microbiology and Immunology). You’ll be joining a friendly and collaborative team with a balance of perspectives, experiences and international backgrounds, with a positive research culture based around curiosity, openness, and inclusion. Regular group meetings and training/networking events offer frequent opportunities to expand both discipline-specific and general research skills e.g. in multivariate statistics, bioinformatics, public engagement, scientific communication and presentation, and programming and image analysis (e.g. R, Matlab, bash, FIJI).
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 instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/
Further reading
• Thompson, C. M. A., Hall, J. P. J., Chandra, G., Martins, C., Saalbach, G., Panturat, S., Bird, S. M., Ford, S., Little, R. H., Piazza, A., Harrison, E., Jackson, R. W., Brockhurst, M. A., & Malone, J. G. (2023). Plasmids manipulate bacterial behaviour through translational regulatory crosstalk. PLOS Biology, 21(2), e3001988. https://doi.org/10.1371/journal.pbio.3001988
• Billane, K., Harrison, E., Cameron, D., & Brockhurst, M. A. (2022). Why do plasmids manipulate the expression of bacterial phenotypes? Philosophical Transactions of the Royal Society B: Biological Sciences, 377(1842), 20200461. https://doi.org/10.1098/rstb.2020.0461
• Cazares, A., Moore, M. P., Hall, J. P. J., Wright, L. L., Grimes, M., Emond-Rhéault, J.-G., Pongchaikul, P., Santanirand, P., Levesque, R. C., Fothergill, J. L., & Winstanley, C. (2020). A megaplasmid family driving dissemination of multidrug resistance in Pseudomonas. Nature Communications, 11, 1370. https://doi.org/10.1038/s41467-020-15081-7
• Oliveira, N. M., Wheeler, J. H. R., Deroy, C., Booth, S. C., Walsh, E. J., Durham, W. M., & Foster, K. R. (2022). Suicidal chemotaxis in bacteria. Nature Communications, 13(1), 7608. https://doi.org/10.1038/s41467-022-35311-4
• Wheeler, J. H. R., Foster, K. R., & Durham, W. M. (2024). Individual bacterial cells can use spatial sensing of chemical gradients to direct chemotaxis on surfaces. Nature microbiology, 9(9), 2308-2322. https://doi.org/10.1038/s41564-024-01729-3