Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids

• DOI: 10.1073/pnas.1400390111
• Publication Date: 2014-03-18T05:41:09Z
• Authors: Hyungjin Eoh; Kyu Y. Rhee
• Keywords: 0301 basic medicine; Carbon Isotopes; Microbial Viability; Fatty Acids; Mycobacterium tuberculosis; Acetates; Isocitrate Lyase; Models, Biological; Carbon; 3. Good health; 03 medical and health sciences; Phenotype; Metabolomics; Citrates; Propionates

Significance

Essentiality is a phenotypic trait of genes frequently used to identify new potential drug targets. However, genes function within the context of complex and extensively interconnected physiologic networks, making it difficult to discern the specific mechanisms responsible for their essentiality. Here, we apply a combination of chemogenetic and metabolomic approaches to resolve the specific biochemical mechanism associated with the bactericidal essentiality of the metabolic enzyme, isocitrate lyase (ICL), for survival of Mycobacterium tuberculosis (Mtb), a chronic intracellular pathogen, on fatty acids, a major carbon source thought to be encountered in vivo. These studies not only provide a systems level insight into the essentiality of Mtb’s ICL but also reveal a previously unrecognized link between propionate metabolism and membrane bioenergetics.