Principal Supervisor: Dr. Elizabeth Fullam, School of Life Sciences
Co-supervisor: Dr. Alex Cameron, School of Life Sciences
PhD project title: Structure/Function studies of nutrient uptake in Mycobacterium tuberculosis – the causative agent of tuberculosis
University of Registration: University of Warwick
Tuberculosis (TB) – caused by Mycobacterium tuberculosis (Mtb) - is one of the leading causes of death worldwide (1). Treatment of TB requires a lengthy, complicated drug regimen, which means that many patients fail to comply with the recommend course of treatment. Poor compliance, in turn, has led to the evolution of multi-drug resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB). In the case of XDR-TB, few, if any, effective therapeutic agents remain. In conjunction with HIV infection, this deadly infection now presents us with a global time bomb that could devastate societies across the globe.
Mtb is different from most bacteria with a distinctive cell wall rich in carbohydrates and lipids and is able to survive intracellularly within the body for decades in a latent state but capable of being reactivated to trigger TB infection. However, whilst we are aware of the ability of Mtb to survive intracellularly, the nutrients that it uses to survive and the processes involved in the import of these nutrients are not fully understood.
Therefore there is an urgent need for a better understanding of this pathogen. We currently do not understand how M. tuberculosis obtains its nutrients and survives and establishes infection in humans (2). This PhD project aims to address this highly topical issue.
The aim of the project is to understand how Mtb obtains and exploits essential nutrients. This will enable us to gain a better understanding of how this organism survives and establishes infection and will allow us to develop tools and techniques for diagnosis purposes.
In this project we want to determine how Mtb obtains and exploits essential nutrients - with the ambitious aim of determining the essentiality of these ABC-transporter and permease uptake systems and determining the structure, function and mechanisms. These studies will provide key structural and mechanistic information on nutrient transport of this pathogen. This research has clear potential to impact on the global health with biotechnological applications.
The student will employ a range of approaches to identify and characterize genes that are essential for nutrient uptake and metabolism in M. tuberculosis. Techniques will include biochemical studies of proteins identified in key nutrient uptake processes (including protein expression and purification, X-ray crystallography, biophysical techniques including isothermal calorimetry, microscale thermophoresis and surface plasmon resonance) alongside bioinformatics approaches.
- M. Niederweis, Nutrient acquisition by mycobacteria. Microbiology 154, 679 (Mar, 2008).
BBSRC Strategic Research Priority: Molecules, Cells and Systems
Techniques that will be undertaken during the project:
Protein expression and purification
Protein Function and biophysical techniques including ITC, MST and SPR
Contact: Dr. Elizabeth Fullam, School of Life Sciences