Understanding isocitrate metabolism in mycobacteria through the use of tailored small-molecule inhibitors

Lead Research Organisation: University of Oxford
Department Name: SABS IDC

Abstract

Tuberculosis (TB) is the ninth most common cause of death worldwide. The World Health Organisation estimates that around 1.6 million people die from TB each year, more than from any other infectious disease. TB is caused by the bacterium Mycobacterium tuberculosis (Mtb), which belongs to a group of organisms known as mycobacteria. Mtb resides primarily in the human body. However, many other mycobacteria are commonly found in soil and water, and do not cause disease in healthy animals or people.
The nutrients available to mycobacteria living in the environment are different to those available in the human body. For example, fatty acids such as cholesterol are a major food source for mycobacteria living in lung tissue, but are much less common in soil. We would therefore expect environmental and host-adapted mycobacteria to metabolise nutrients differently. Understanding the differences in metabolism between environmental and host-adapted mycobacteria will help us to find out why some mycobacteria succeed at surviving in the human body and causing disease, while other mycobacteria fail.
Isocitrate is produced when mycobacteria break down various nutrients, including glucose and fatty acids. Mycobacteria have two pathways for the metabolism of isocitrate. One of these pathways, the glyoxylate shunt, is much more active when mycobacteria are metabolising fatty acids than when they are metabolising glucose. The glyoxylate shunt is essential for the survival of Mtb in lung tissue, and has therefore been of significant interest to the research community. However, this pathway has not been studied in mycobacteria other than Mtb. We would like to quantify the balance between the two pathways under various environmental conditions and in a range of mycobacterial species. This will tell us if changes in isocitrate metabolism are a necessary part of host adaptation, furthering our understanding of the processes involved in Mtb pathogenicity and persistence.
Chemical tools are useful for investigating biological pathways, as they provide an independent, orthogonal way to probe enzyme activity and metabolism. As part of this project, we hope to develop a new set of selective tools to study isocitrate metabolism in mycobacteria. If successful, the same methodology could be used in the future to probe a wide range of metabolic processes in mycobacteria, many of which are currently poorly characterised. Understanding these processes could enable significant progress in the fight against TB and other mycobacterial diseases, including leprosy, Buruli ulcer and bovine TB.
This project, which is a collaboration between the Francis Crick Institute, GSK and Oxford Chemistry, falls within the EPSRC Chemical Biology and Biological Chemistry research area.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R512333/1 01/10/2017 30/09/2021
1941435 Studentship EP/R512333/1 01/10/2017 30/09/2021 Stephanie Lovell-Read