Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis

A - Papers appearing in refereed journals

Borah, K., Mendum, T. A., Hawkins, N. D., Ward, J. L., Beale, M. H., Larrouy-Maumus, G., Bhatt, A., Moulin, M., Haertlein, M., Strohmeier, G., Pichler, H., Forsyth, V. T., Noack, S., Goulding, C. V., McFadden, J. and Beste, D. J. V. 2021. Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis. Molecular systems biology. 17 (5), p. e10280. https://doi.org/10.15252/msb.202110280

AuthorsBorah, K., Mendum, T. A., Hawkins, N. D., Ward, J. L., Beale, M. H., Larrouy-Maumus, G., Bhatt, A., Moulin, M., Haertlein, M., Strohmeier, G., Pichler, H., Forsyth, V. T., Noack, S., Goulding, C. V., McFadden, J. and Beste, D. J. V.
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.

Year of Publication2021
JournalMolecular systems biology
Journal citation17 (5), p. e10280
Digital Object Identifier (DOI)https://doi.org/10.15252/msb.202110280
Open accessPublished as ‘gold’ (paid) open access
FunderBiotechnology and Biological Sciences Research Council
Wellcome Trust
Funder project or codeBB/T007648/1
Publisher's version
Output statusPublished
Publication dates
Online04 May 2021
Publication process dates
Accepted31 Mar 2021
PublisherEmbo Press

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