Bacteria are surrounded by a mesh-like cell wall which protects bacteria from bursting due to their high internal pressure of turgor pressure, like how a thick bicycle tyre supports and reinforces the inflated inner tube. Many of our best antibiotics target the protein machines that remodel the bacterial cell wall, as defects or holes in the cell wall result in explosive cell lysis and death. 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 molecular and biophysical principles by which proteins elongate, divide and remodel the cell wall without bursting the cell. To do this we use single molecule tracking and super-resolution microscopy to follow the activity of individual proteins directly in living cells as they build the cell wall.
WHAT WILL YOU BE DOING FOR YOUR PHD RESEARCH?
The final PhD project will be developed with the student according to their interests and skill set, while fitting within the general lab theme of using advanced microscopy to investigate how bacteria remodel their cell envelope.
One possible PhD topic that we are excited about concerns the final step of cell division in Gram-positive bacteria, called scission. In order to divide, Gram-positive bacteria first build a cross-wall at the middle of the cell, and then tiny molecular scissors called cell wall hydrolases precisely cut down the middle of that cross-wall to separate the cell into two daughter cells . The slightest error in positioning of these molecular scissors would result in explosive cell death due to holes in the cell wall. How hydrolases cut exclusively along the middle of the cell septum is arguably one of the greatest puzzles of bacterial spatial organization and would form an excellent topic for a PhD project using single molecule tracking to follow the activity of individual cell wall hydrolases as they cut the division septum in two.
Principal techniques used in our lab include:
- Bacterial genetics and molecular biology
- Single molecule tracking and super-resolution microscopy
- Image analysis and data science - to analyse complex microscopy datasets.
There is also the opportunity to collaborate with Bart Hoogenboom at UCL during the PhD, to use atomic force microscopy to investigate how cell wall properties change over time in live bacteria, especially in the context of how cell wall hydrolases remodel the cell wall.
ABOUT OUR LAB
The Holden lab is a diverse group of biologists, biophysicists and microscopists who investigate fundamental mechanisms of bacterial cell envelope remodelling using advanced light microscopy (see e.g. [2–4]). We are based at the brand new £54M Interdisciplinary Biosciences Building at the School of Life Sciences, University of Warwick, which brings together researchers from microbiology, eukaryotic cell biology and neuroscience in a single interdisciplinary, collaborative environment with state-of-the-art facilities.
IS THIS PROJECT RIGHT FOR YOU?
This project would suit students from either biology- or physics-allied disciplines: the principal requirements for recruitment are outstanding potential, passion for fundamental science and a desire to work across disciplinary boundaries. Extensive interdisciplinary training will be provided and both the project and the training can be tailored to the initial skillset of the student.
 T. Uehara, T.G. Bernhardt, Current Opinion in Microbiology. 14 (2011) 698–703.
 K.D. Whitley et al., Nature Communications. 12 (2021) 2448..
 K.D. Whitley et al., Nat Protoc. 17 (2022) 847–869.
 A.W. Bisson-Filho et al., Science. 355 (2017) 73
BBSRC Strategic Research Priority: Understanding the rules of life – Microbiology.
Techniques that will be undertaken during the project:
- Single molecule fluorescence microscopy, super-resolution fluorescence microscopy (supervision training)
- Quantitative image and data analysis with Python and ImageJ (supervision training).
- Bacterial cell biology, bacterial genetics, molecular biology (supervision training)