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A multidisciplinary approach to elucidate how TB obtains and uses essential energy sources

Primary Supervisor: Dr Elizabeth Fullam, School of Life Sciences

Secondary supervisor: Professor Alex Cameron/ Professor Matthew Gibson

PhD project title: A multidisciplinary approach to elucidate how TB obtains and uses essential energy sources

University of Registration: University of Warwick

Project outline:

Tuberculosis (TB) is a major global health challenge. TB is now the leading cause of death from a single infectious agent worldwide killing more people than HIV and malaria combined. As the number of drug-resistant TB infections escalates and the current front-line drugs become ineffective we urgently need to develop new strategies to control the TB epidemic. In order to develop new interventions we need to understand the fundamental biology and physiology of Mycobacterium tuberculosis – the causative agent of TB.

Mycobacterium tuberculosis is a very unusual pathogen and has evolved an incredible ability to survive latently in the human host for decades, capable of reactivating to trigger TB infection. However, our knowledge of the nutrients/energy sources that M. tuberculosis uses and the mechanisms that are involved in their uptake and subsequent metabolism is poorly understood.

Research in Dr Elizabeth Fullam’s laboratory is focused on understanding the molecular mechanisms that Mtb uses to obtain and process these essential nutrients. We are then using this fundamental information to develop routes and strategies to target these processes to develop new anti-tubercular therapeutics/diagnostics. To do this we use a range of multidisciplinary approaches in the lab which include:

  • X-ray crystallography and related structural biology techniques to determine the function and mechanism of Mtb transporters and metabolising enzymes

  • Biochemicalandbiophysicalapproaches(e.g.microscalethermophoresis,surface plasmon resonance, biolayer interferometry) to determine protein function

  • Targeted gene mutagenesis and microbiology methods to study the fundamental role of these Mtb uptake transporters and metabolising enzymes

  • Synthetic chemistry and chemoenzymatic methods to develop new tools to probe mechanisms and develop new compounds that can either kill or detect Mtb

Overall this multidisciplinary approach uses the latest techniques to probe important, fundamental mechanisms of this major global pathogen. Unravelling these processes will lead to valuable new insights into what Mtb ‘eats’ and how it uses these energy sources that can potentially be exploited to develop new molecules with novel modes of action that either kill Mtb or can be used for detection/diganosis.

References:

  • 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

  • Guy CS, Gibson MI, Fullam E, “Targeting extracellular glycans: Tuning multimeric boronic acids for pathogen-selective killing of Mycobacterium tuberculosis” Chem. Sci. (2019) 10 5935-5942

  • 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

BBSRC Strategic Research Priority: Understanding the Rules of Life: Microbiology & Structural Biology

Techniques that will be undertaken during the project:

  • Molecular biology (cloning, mutagenesis)

  • Protein expression and purification

  • Protein crystallisation

  • Structure determination (including X-ray crystallography, cryo-EM)

  • Protein Function and biophysical techniques including ITC, MST and SPR

  • Ligand screening assays

  • Enzyme assays

  • Proteomics

  • Targeted gene mutagenesis

  • Microbiology training – including working at containment levels 2 and 3

  • Antibiotic testing (MIC/MBC determination)

  • Chemoenzymatic synthesis

  • Synthetic chemistry

  • Bioinformatics

Contact: Dr Elizabeth Fullam, University of Warwick