Structural insights into how Mycobacterium tuberculosis interacts with human cells

Department: Department of Respiratory Sciences, University of Leicester

Supervisors: Dr Helen O'Hare, Dr Abhinav Koyamangalath Vadakkepat

Applications accepted all year round

Self-Funded PhD Students Only

About the Project

Project: Mycobacterium tuberculosis is the leading global cause of death from a single infectious agent. It is a highly specialised human pathogen and is able to adapt to changing conditions in human macrophages and granulomas in order to subvert immune defences.

Studying M. tuberculosis virulence proteins will shed light on how this bacterium is so successful and identify new opportunities for drug development to improve treatment of tuberculosis.

Recent work from our labs includes (1) identification of a sensor-kinase complex that allows the bacterium to sense human amino acids and adapt its metabolism accordingly and (2) identification of enzyme involved in cell envelope synthesis that is linked to tuberculosis transmission.

Key goals are to determine the structure of the protein kinase G signalling complex (1), which is one of the most widespread of bacterial serine threonine protein kinases; and (2) understanding the function of unknown enzyme FadB4 and its relationship to bacterial cell surface hydrophobicity and interaction with macrophages.

Training opportunities:

The student will gain advanced skills in structural biology, working with the Leicester Institute for Structural and Chemical Biology:

• Cloning and recombinant protein production, purification and analysis,
• Protein biophysics (stability, binding assay for small molecules (ligands), protein-protein interactions)
• Enzyme assay/kinase assay
• Structure determination by X-ray crystallography and/or Cryo electron microscopy

The student will gain specialist skills in microbiology of infection, working with the Leicester TB Research Group:

• Culture and genetic modification of Mycobacterium (gene knockout and complementation)

Output: this is an opportunity for a self-funded student to improve knowledge and treatment of tuberculosis and gain advanced skills in structural biology and microbiology.