Metabolomics of Central Carbon Metabolism in Mycobacterium tuberculosis

Abstract

Metabolism is a biochemical activity of all cells, thought to fuel the physiologic needs of a given cell in a quantitative, rather than qualitatively specific, manner. Mycobacterium tuberculosis is a chronic facultative intracellular pathogen that resides in humans as its only known host and reservoir. Within humans, M. tuberculosis resides chiefly in the macrophage phagosome, the cell type and compartment most committed to its eradication. M. tuberculosis thus occupies the majority of its decades-long life cycle in a state of slowed or arrested replication. At the same time, M. tuberculosis remains poised to reenter the cell cycle to ensure its propagation as a species. M. tuberculosis has thus evolved its metabolic network to both maintain and propagate its survival as a species within a single host. Knowledge of the specific ways in which its metabolic network serves these distinct though interdependent functions, however, remains highly incomplete. In this article we review existing knowledge of M. tuberculosis's central carbon metabolism as reported by studies of its basic genetic and biochemical composition, regulation, and organization, with the hope that such knowledge will inform our understanding of M. tuberculosis's ability to traverse the stringent and heterogeneous niches encountered in the host.

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

“…Even as a non-replicating bacilli with minimal metabolic activity, Mtb has evolved unique metabolic adaptability to the host-imposed stringent niches in order to preserve its survival and ability to ensure transmission to a new host [ 130 ]. CCM provides energy and essential biosynthetic precursors, thus playing a key role in Mtb pathogenicity [ 131 ], and Mtb demonstrated the ability to use a plethora of organic substrates, such as carbohydrates, lipids, amino acids, and simple organic acids, to fuel it. While active Mtb requires carbohydrates as the main carbon source, Mtb in a latent phase that resides within the macrophage phagolysosome, where oxygen and nutrient depletion induce a massive metabolic rearrangement [ 132 ].…”

Synthesis, Structure–Activity Relationship, and Mechanistic Studies of Aminoquinazolinones Displaying Antimycobacterial Activity

“…All considered together, the results from the MOA studies suggest that the aminoquinazolinone series potentially exert its inhibitory effect by dysregulating the glycerol dissimilation pathway, 31 leading to the toxic accumulation of sugar phosphates such as G3P and DHAP in Mtb . 28 When glycerol is not used as a carbon source by Mtb in vivo , compounds with such MOA do not show efficacy in the mouse model.…”

Infect and Inject: How Mycobacterium tuberculosis Exploits Its Major Virulence-Associated Type VII Secretion System, ESX-1

“…Interestingly, to counter host-imposed nutrient restrictions, M. tuberculosis can synthesize most of the essential nutrients for its growth, but it is also capable of acquiring nutrients from the host. M. tuberculosis can obtain carbon, nitrogen, and some amino acids from the host (41, 43, 44), but intriguingly, it is not able to acquire arginine, methionine, or leucine from the host (45–47). In the Jacobs laboratory, we have demonstrated that arginine or methionine auxotrophy is bactericidal to M. tuberculosis in vitro and in vivo , both in macrophages and in mice (45, 46), whereas leucine auxotrophy is bacteriostatic (45–47).…”