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Towards new drugs and diagnostics for tuberculosis: Elucidating and exploiting essential pathways in the Mycobacterium tuberculosis pathogen

Primary Supervisor: Dr Elizabeth Fullam, School of Life Sciences

Secondary supervisor: Project dependent: Professor Alex Cameron/ Professor Matthew Gibson/ Dr Phill Stansfeld

PhD project title: Towards new drugs and diagnostics for tuberculosis: Elucidating and exploiting essential pathways in the Mycobacterium tuberculosis pathogen

University of Registration: University of Warwick

Project outline:

Tuberculosis (TB) is a major global health challenge. TB is the leading cause of death worldwide from a single bacterial pathogen 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 strategies and interventions to combat this deadly pathogen we need to understand the fundamental biology and biochemistry of Mycobacterium tuberculosis – the causative agent of TB.

Mycobacterium tuberculosis (Mtb) is a very unusual pathogen and has evolved an incredible ability to survive in the human host for decades. However, our knowledge of how Mtb obtains and uses nutrients and essential energy sources to survive is poorly understood.

Research in our 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.

The main themes in our lab are: 1) determining the molecular mechanisms of enzymes involved in key transport and metabolic pathways in Mtb 2) development of new chemical tools and probes to understand the Mtb pathogen, 3) discovering new approaches that can either kill and/or detect Mtb

We use a multidisciplinary approach that includes biochemistry, biophysics, structural biology, microbiology and molecular genetics, synthetic chemistry and chemoenzymatic methods, analytical chemistry and molecular modelling. Overall this multidisciplinary approach uses the latest techniques to probe important, fundamental mechanisms of this major global pathogen. Some examples of our recent exciting findings are listed in the references below. Unravelling these essential processes will lead to valuable new insights into what Mtb ‘eats’ and how it uses these energy sources that can be exploited to develop new molecules with novel modes of action that either kill Mtb or can be used for detection/diagnosis.

References:

  1. Karlikowska M, Singh A, Bhatt A, Ott S, Bottrill AR, Besra G, Fullam E ‘Biochemical and phenotypic characterisation of the Mycobacterium smegmatis transporter UspABC’ Fullam, The Cell Surface (2021), 7 100052
  2. Furze CM, Delso I, Casal E, Guy CS, Seddon C, Brown CM, Parker HL, Radhakrishnan A, Pacheco-Gomez R, Stansfeld PJ, Angulo J, Cameron AD, Fullam E ‘Unravelling the specificity and structural basis of trehalose recognition by the mycobacterial LpqY-SugABC transporter’ J Biol Chem (2021), 296, 100307
  3. Parker HL, Tomas RMF, Furze CM, Guy CS and Fullam E ‘Asymmetric trehalose analogues to probe disaccharide processing pathways in mycobacteria’ Biomol. Chem., 2020,18, 3607-3612
  4. 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 
  5. Guy CS, Murray K, Gibson MI, Fullam E, ‘Dimeric benzoboroxoles for targeted activity against Mycobacterium tuberculosis’ Org. Biomol. Chem. (2019) 17 9524
  6. Guy CS, Gibson MI, Fullam E, “Targeting extracellular glycans: Tuning multimeric boronic acids for pathogen-selective killing of Mycobacterium tuberculosis Sci. (2019) 10 5935-5942
  7. Radhakrishnan A, Furze CM, Ahangar MS, Fullam E “A GFP-strategy for efficient recombinant protein overexpression and purification in Mycobacterium smegmatisRSC Advances (2018) 8 33087-33095
  8. Ahangar MS, Furze CM, Guy CS, Cooper C, Maskew KS, Graham B, Cameron AD, Fullam EStructural and functional determination of homologs of the Mycobacterium tuberculosis N-acetylglucosamine-6-phosphate deacetylase, NagA, enzyme” Biol Chem. (2018) 293 9770-9783
  9. Fullam E, Proke I, Futterer K, Besra GS. “Structural and Functional Analysis of the solute-binding protein UspC from Mycobacterium tuberculosisOpen 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 production 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
      • Molecular modelling
      • Bioinformatics

      Contact: Dr Elizabeth Fullam, University of Warwick