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Single molecule biology of bacterial cell wall remodelling
Secondary Supervisor(s): Professor David Roper, or Professor Phil Stansfield (depending on project undertaken)
University of Registration: University of Warwick
BBSRC Research Themes: Understanding the Rules of Life (Microbiology, Structural Biology)
Project Outline
Bacteria are surrounded by a mesh-like cell wall which protects them from bursting due to their high internal pressure of turgor pressure. A better understanding of the fundamental principles of bacterial cell wall remodelling will help us to understand how bacteria resist antibiotics and may help identify new targets for antibiotic drug development.
In the Holden lab at Warwick University, we study the biology and biophysics of bacterial cell wall remodelling in Bacillus subtilis and Escherichia coli (see e.g. [1–3]). We mostly focus on two related protein machines: the elongasome, responsible for growing the bacterial cell wall by adding new material to it, and the divisome, responsible for dividing the cell by building a mid-cell crosswall (septum). We investigate how nanoscale cell wall synthesis complexes precisely build and sculpt a comparatively massive micron-sized bacterial cell wall. This problem bridges bacteriology, biophysics, and microscopy.
Principal techniques used in our lab include:
- In vivo single molecule microscopy and super-resolution microscopy to image the nanoscale organisation and dynamics of cell wall synthesis,
- In vitro single molecule fluorescence methods to follow the structural conformational dynamics of individual cell wall remodelling proteins,
- Molecular microbiology, bacterial genetics and bacterial cell biology methods - to understand how proteins work at the molecular and cellular level,
- Image analysis and data science - to analyse complex microscopy datasets.
About our Lab
The Holden lab is a diverse group of scientists from disciplines including biology, biophysics and microscopy who investigate fundamental mechanisms of bacterial cell envelope remodelling using advanced light microscopy. We are based at the new £54M Interdisciplinary Biosciences Building at the School of Life Sciences, University of Warwick, which brings together interdisciplinary researchers in a single interdisciplinary, collaborative environment with state-of-the-art facilities. Further information about the lab can be found at https://holdenlab.github.io/
We take a team science approach and are highly collaborative with a wide network of outstanding collaborators at Warwick and across the world, including as far away as Australia. During the PhD there will be substantial opportunity to engage in collaborative research.
Is this project right for you?
This project would suit students from biology- or physics-allied disciplines, such as biochemistry, biomedical sciences or physics. The principal requirements for recruitment are outstanding potential, passion for fundamental science and a desire to work across disciplinary boundaries. Interdisciplinary training will be provided and both the project and the training can be tailored to the initial skillset of the student.
What will you be doing for your PhD Research?
The final PhD project will fit broadly within the research directions described above and will be developed with the student according to their interests and skill set within a collaborative research environment. PhDs could also involve substantial work in the labs of potential co-supervisors Professor David Roper (biochemistry) or Professor Phill Stansfeld (computational molecular dynamics). We urge students interested in the project to get in contact at earliest possible opportunity (seamus.holden@warwick.ac.uk).
References
[1] K.D. Whitley, J. Grimshaw, D.M. Roberts, E. Karinou, P.J. Stansfeld, S. Holden, Peptidoglycan synthesis drives a single population of septal cell wall synthases during division in Bacillus subtilis, Nat. Microbiol. (2024) 1–11. https://doi.org/10.1038/s41564-024-01650-9.
[2] S. Middlemiss, M. Blandenet, D.M. Roberts, A. McMahon, J. Grimshaw, J.M. Edwards, Z. Sun, K.D. Whitley, T. Blu, H. Strahl, S. Holden, Molecular motor tug-of-war regulates elongasome cell wall synthesis dynamics in Bacillus subtilis, Nat. Commun. 15 (2024) 5411. https://doi.org/10.1038/s41467-024-49785-x.
[3] C. Vanhille-Campos, K.D. Whitley, P. Radler, M. Loose, S. Holden, A. Šarić, Self-organization of mortal filaments and its role in bacterial division ring formation, Nat. Phys. (2024) 1–9. https://doi.org/10.1038/s41567-024-02597-8.
