Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a major threat to human health and is now the world’s leading cause of death from a single infectious agent. The latest World Health Organisation report states that in 2018 alone TB claimed the lives of ~1.6 million people and that ~ 10 million people became ill with TB. The incidences of drug resistant strains of Mtb are increasing at an alarming rate and include the emergence of Mtb strains that are not treatable with any of the current antibiotic regimens. Therefore, there is an urgent need for the development of new strategies to reduce the TB burden. To do this, we need a much better understanding of the basic biology of this global pathogen.
Mtb is a very unusual pathogen that has developed a highly effective strategy to survive within the human host for decades. However, we do not have a good understanding as to how Mtb can thrive within this ‘hostile’ environment. In particular we do not know what Mtb uses as an energy source and ‘eats’ to survive. This project aims to address this lack of knowledge and determine which nutrients are available to Mtb and how Mtb exploits and uses them: i.e. how are these nutrients transported and metabolised.
In this PhD project a mixture of biochemical, structural and chemical approaches will be used to functionally characterise Mtb transporters that are involved in the uptake of essential nutrients enabling Mtb to scavenge nutrients to survive. This project will involve the expression and purification of recombinant Mtb transport proteins, and the characterisation of substrate recognition through a combination of biochemical assays and structural analysis (e.g. X-ray crystallography). Overall this project will provide important insights into the role of the Mtb transporters which may lead to new avenues to explore in TB drug discovery/diagnostic efforts.
Key experimental skills involved include:
Molecular biology (cloning, mutagenesis)
Protein expression and purification
Structure determination (including X-ray crystallography, cryo-EM)
Protein Function and biophysical techniques including ITC, MST and SPR
Ligand screening assays
Targeted gene mutagenesis
The deadline for applications is 17:00 (GMT) 17th February 2020
This studentship covers Home/ EU or Overseas tuition fees and provides a stipend of at least £15,009 for 3 years
Fenn JS, Nepravishta R, Guy CS, Harrison J, Angulo J, Cameron AD, Fullam E, ‘Structural basis of glycerophosphodiester recognition by the Mycobacterium tuberculosis substrate-binding protein UgpB’ ACS Chemical Biology (2019) 14 1879- 1887
Radhakrishnan A, Furze CM, Ahangar MS, Fullam E “A GFP-strategy for efficient recombinant protein overexpression and purification in Mycobacterium smegmatis” RSC Advances (2018) 8 33087-33095
Ahangar MS, Furze CM, Guy CS, Cooper C, Maskew KS, Graham B, Cameron AD, Fullam E “Structural and functional determination of homologs of the Mycobacterium tuberculosis N-acetylglucosamine-6-phosphate deacetylase, NagA, enzyme” J. Biol Chem. (2018) 293 9770-9783
Fullam E, Proke I, Futterer K, Besra GS. “Structural and Functional Analysis of the solute-binding protein UspC from Mycobacterium tuberculosis’ Open Biol. (2016) DOI: 10.1098/rsob.160105
How good is research at University of Warwick in Agriculture, Veterinary and Food Science?
FTE Category A staff submitted: 12.60
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