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Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis.

Borah, Khushboo; Bhatt, Apoorva; Moulin, Martine; Haertlein, Michael; Strohmeier, Gernot; Pichler, Harald; Noack, Stephan; McFadden, Johnjoe

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Khushboo Borah

Apoorva Bhatt

Martine Moulin

Michael Haertlein

Gernot Strohmeier

Harald Pichler

Stephan Noack

Johnjoe McFadden


The co-catabolism of multiple host-derived carbon substrates is required by Mycobacterium tuberculosis (Mtb) to successfully sustain a tuberculosis infection. However, the metabolic plasticity of this pathogen and the complexity of the metabolic networks present a major obstacle in identifying those nodes most amenable to therapeutic interventions. It is therefore critical that we define the metabolic phenotypes of Mtb in different conditions. We applied metabolic flux analysis using stable isotopes and lipid fingerprinting to investigate the metabolic network of Mtb growing slowly in our steady-state chemostat system. We demonstrate that Mtb efficiently co-metabolises either cholesterol or glycerol, in combination with two-carbon generating substrates without any compartmentalisation of metabolism. We discovered that partitioning of flux between the TCA cycle and the glyoxylate shunt combined with a reversible methyl citrate cycle is the critical metabolic nodes which underlie the nutritional flexibility of Mtb. These findings provide novel insights into the metabolic architecture that affords adaptability of bacteria to divergent carbon substrates and expand our fundamental knowledge about the methyl citrate cycle and the glyoxylate shunt.

Journal Article Type Article
Acceptance Date Mar 31, 2021
Online Publication Date May 4, 2021
Publication Date 2021-05
Publicly Available Date May 30, 2023
Journal Molecular Systems Biology
Publisher Wiley
Volume 17
Issue 5
Article Number ARTN e10280
Keywords chemostat; metabolic flux; metabolism; Mycobacterium tuberculosis; tuberculosis
Publisher URL


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