Background
Bacteria are a major cause of infectious disease. For example, tuberculosis, caused by the bacterium Mycobacterium tuberculosis, is one of the top 10 causes of death worldwide (World Health Organisation; 2016). Many bacteria are increasingly resistant to our best antibiotics so we may soon have infectious disease without viable treatments.
We typically study bacteria in the laboratory that are grown suspended in a nutrient broth, but during infection and in the environment bacteria will often form biofilms, which are bacterial aggregates growing on a surface. Biofilms growing on medical implants can be a major complication of surgery and there is evidence bacteria in a biofilm are more resistant to antibiotics.
Originally, biofilms were thought to be simply a mass of bacteria. but it is now clear biofilms are much more sophisticated than that. They possess an ordered structure with layers of bacteria encased in a complex extracellular matrix and there is a steep gradient in oxygen concentration from their surface to their foundation. The species at the bottom are often metabolically dormant but capable of rapid reactivation at a later time.
The vast majority of our knowledge on bacterial biology is based on them growing in solution (the planktonic form) and there is a dearth of techniques for growing biofilms or studying them once grown. This project aims to address these questions using biomaterials chemistry, with a particular focus on mycobacteria, the causative agents of tuberculosis and leprosy.
Objectives
- Use materials chemistry to create surfaces with defined characteristics that allow the growth of biofilms that mimic those found in vivo. Possible surfaces include ones based on gel chemistry to recapitulate the extracellular matrix.
- Use bacterial genetics to fluorescently tag M. smegmatis, a harmless close-relative of tuberculosis, which behaves similarly in forming biofilms.
- Grow the generated strains of M. smegmatis on our surfaces and image the changes that occur as the biofilm develops and the bacteria respond to their new environment.
- Use super-resolution microscopy and cryo-electron microscopy (cryoEM) to image the subcellular location of the key enzymes and morphological changes as the biofilm develops.
- Explore how the biofilm responds to clinically relevant antibiotics such as bedaquiline, a recently approved drug against tuberculosis.
Experimental approach
This work is interdisciplinary between chemistry, biophysics and microbiology. Jamie Blaza uses cryoEM to understand the bioenergetics and biology of bacterial pathogens, Chris Spicer works on the synthesis of biomaterials with defined and tunable characteristics and Christoph Baumann uses single-molecule mechanics and super-resolution microscopy to probe the spatio-temporal organisation and biophysical properties of bacterial cell envelopes. Tools and insights from these interdisciplinary backgrounds will be leveraged to understand key biological questions on how the bacteria attach themselves to surfaces, how they differ through the depth of the biofilm, and how the biofilm protects the bacteria from antibiotic action.
Novelty
It is clear that the material a biofilm grows on has important implications for its characteristics but this has been little explored up till now. By combining materials chemistry, microbiology, and biophysics, we will be able to systematically explore these relationships and create a powerful platform to offer the field.
Training
This project is an excellent opportunity for a chemist with an interest in the biological sciences to engage with microbiology in a supportive environment. They will be able to learn materials chemistry, bacteriology, and cutting-edge imaging techniques such as cryoEM and super-resolution microscopy. Interdisciplinary science is a growing field and the student will have the opportunity to learn how to communicate and operate effectively between scientists from diverse backgrounds.
All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/
The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/.
For more information about the project, click on the supervisor's name above to email the supervisor. For more information about the application process or funding, please click on email institution
This PhD will formally start on 1 October 2021. Induction activities will start on 27 September.
To apply for this project, submit an online PhD in Chemistry application: https://www.york.ac.uk/study/postgraduate/courses/apply?course=DRPCHESCHE3
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