Borah, K, Mendum, TA, Hawkins, ND, Ward, JL, Beale, MH, Larrouy-Maumus, G, Bhatt, A, Moulin, M, Haertlein, M, Strohmeier, G, Pichler, H, Forsyth, VT ORCID: https://orcid.org/0000-0003-0380-3477, Noack, S, Goulding, CW, McFadden, J and Beste, DJV (2021) Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis. Molecular Systems Biology, 17 (5). e10280 - ?.

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Abstract

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.

Item Type: Article
Additional Information: © 2021 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Uncontrolled Keywords: chemostat; metabolic flux; metabolism; Mycobacterium tuberculosis; tuberculosis
Subjects: R Medicine > R Medicine (General)
R Medicine > R Medicine (General) > R735 Medical education. Medical schools. Research
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Depositing User: Symplectic
Date Deposited: 04 Jun 2021 11:33
Last Modified: 11 Jun 2021 10:02
URI: https://eprints.keele.ac.uk/id/eprint/9662

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