Mycobacterium tuberculosis Systems and Chemical Biology

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

We aim to identify and characterize metabolic components from Mycobacterium 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 discover novel antibiotics that are better than the ones in current use.
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 must participate in novel metabolic pathways. In addition, some of these essential enzymes will lack counterparts in humans and therefore might represent attractive new targets for antibiotic research.
We are very interested in discovering how M. tuberculosis survives in host, evades the immune system and resist to antibiotic therapy. To achieve this, we are using state-of-the-art approaches to integrate several aspects of M. tuberculosis–host biology.

Technical Summary

The aim of our research is to uncover new physiology and new biochemistry that helps Mycobacterium tuberculosis to survive in the host and to avoid the immune system. In addition, we are committed with the characterization and development of novel anti-infectives to treat human Tuberculosis. Novel small molecule therapeutics for Tuberculosis could help save as many as 1.5 million lives yearly.
Our approach involves the use of enzymology, mycobacteriology, immunology, structural biology, chemical biology and accurate-mass LC-MS-based metabolomics.
Functional Genomics: To uncover new pathways and chemical reactions we are applying metabolomic and enzymology approaches to orphan mycobacterial enzymes, trying to determine their function and their contribution to mycobacterial metabolism and fitness. These experiments are further complemented by structural biology and mycobacterial genetics.
Drug Discovery: Mechanistic enzymology and metabolomics are also been used to characterize and validate and novel anti-infective targets in Mycobacterium tuberculosis and develop novel and better inhibitors. Mechanism-of-action and “on-target” validation studies using metabolomics are underway. Selected inhibitors will be tested against mycobacteria to verify their potential as novel anti-infectives.
Systems Biology: Stable isotope labelling and metabolomics are employed to define the flux through known biochemical pathways and the role of these pathways in Mycobacterium tuberculosis survival in culture and in macrophages. In addition, isotope tracing methods are also been used to map new metabolic pathways in mycobacteria. Some of these pathways might represent attractive targets for the development of novel drugs. These experiments are further complemented by the use of small molecules and genetic mutants.

Publications

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Belardinelli JM (2014) Biosynthesis and translocation of unsulfated acyltrehaloses in Mycobacterium tuberculosis. in The Journal of biological chemistry

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Larrouy-Maumus G (2013) Discovery of a glycerol 3-phosphate phosphatase reveals glycerophospholipid polar head recycling in Mycobacterium tuberculosis. in Proceedings of the National Academy of Sciences of the United States of America