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Sucking the energy out of TB: cryoEM and functional biophysics to target respiratory complexes in Mycobacterium tuberculosis

Project Description

Tuberculosis (TB) is a devastating disease caused by the bacterium Mycobacterium tuberculosis and is one of the top 10 causes of death worldwide (World Health Organisation; 2016). Current treatments require administering a cocktail of antibiotics over an extended period with unpleasant side-effects; drug resistance threatens to render even these treatments ineffective. A recently developed and unprecedented strategy to kill tuberculosis is to target the bioenergetics of the organism, which provides the energy the bacteria needs to infect cells. This project will focus on the bd oxidase, which is a crucial bioenergetic enzyme for allowing the bacteria to scavenge oxygen in low oxygen environments and possibly to break down the harmful hydrogen peroxide generated by the host as an immune response. Compounds are currently under active development to inhibit the bd oxidase as drug candidates.

The student will use cutting-edge biophysical methods to understand how this enzyme works on both structural and functional levels. They will receive training in bacteriology, membrane protein biochemistry, cryoEM (both data collection and image processing), and kinetic modelling/signal processing using the Python programming language with the NumPy/SciPy libraries.

- Building on a protocol developed in the lab, isolate the bd oxidase from a harmless and fast growing mycobacterial model organism.
- Prepare cryogrids of the isolated enzyme and image them using new electron cryo-microscope at the University of York.
- Process the particle images to obtain a structural model of the enzyme for interpretation.
- Apply rapid and steady-state kinetics to measure the enzymatic reactions. Use kinetic modelling in Python to create a unified model for the enzyme and use it to test structurally inspired mutations.
- Use haem absorption spectra and signal processing techniques to measure electron flux to the bd oxidase in native membranes to understand its role in living cells.

Funding Notes

This is a BBSRC WR DTP studentship fully-funded for 4 years and covers: (i) a tax-free stipend at the standard Research Council rate (around £15,000 per year) (ii) research costs, and (iii) tuition fees at the UK/EU rate. The studentship is available to UK and EU students who meet the UK residency requirement (to have been residing in the UK for at least 3 years continuously prior to the start of the PhD).


ENTRY REQUIREMENTS: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with backgrounds in any biological, chemical, and/or physical science, or students with mathematical backgrounds who are interested in using their skills in addressing biological questions.

How good is research at University of York in Biological Sciences?

FTE Category A staff submitted: 44.37

Research output data provided by the Research Excellence Framework (REF)

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