Mycobacterium tuberculosis systems and chemical biology

Lead Research Organisation: The Francis Crick Institute

Abstract

Human tuberculosis is currently the infectious disease that kills the most, with an estimated 1.8 million deaths in 2015, surpassing even deaths associated with HIV/AIDS. Recently, only a few new drugs have been developed and no new vaccine is in the horizon. It is believed that our lack of understanding of Mycobacterium tuberculosis and of the disease is largely responsible for our current failure in developing new drugs and vaccines. Our research is aimed at mapping and understanding how M. tuberculosis acquires nutrients during infection, how these are metabolised, and finally how antibiotics act against this bacterium. This is particular important, as M. tuberculosis is very different from the vast majority of other bacteria that cause human disease. One key aspect of our research which is almost unique is the use of a chemical method, called mass spectrometry, to try to understand M. tuberculosis metabolism and antibiotic action.

Technical Summary

This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)

Despite significant progress in tuberculosis research in the last decades we still fail to understand basic principles of the disease. Lack of basic understanding of Mycobacterium tuberculosis is thought to be one of the main reasons why we experience a number of difficulties in developing new drugs and new vaccine candidates. As tuberculosis continues to kill nearly 2 million people per year and multi-drug resistance is on the rise, we urgently need new research approaches to accelerate the development of novel treatments to revert this epidemic.
We aim to uncover and characterize metabolic components from M. tuberculosis responsible for its unique ability to survive in humans and cause disease. In addition, we are interested in understanding how antibiotics act against M. tuberculosis, how is resistance developed and how we can accelerate the discovery of novel and improved antibiotics. To do this in an effective and unbiased fashion we take advantage of liquid chromatography-mass spectrometry metabolomics, as our chief experimental technique. Metabolomics allows simultaneous, unbiased, and quantitative interrogation of hundreds of small molecules in parallel, which in turn allow us to examine mycobacterial metabolism at very high resolution.
Enzymes are responsible for most of the activities in any cell, from bacteria to man. We are particularly interested in novel enzymes from M. tuberculosis that likely belong to novel metabolic pathways. In addition, some of these essential enzymes will lack counterparts in humans and therefore might represent attractive new targets for antibiotic development.

Publications

10 25 50