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Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis

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...

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Autores principales: Borah, Khushboo, Mendum, Tom A, Hawkins, Nathaniel D, Ward, Jane L, Beale, Michael H, Larrouy‐Maumus, Gerald, Bhatt, Apoorva, Moulin, Martine, Haertlein, Michael, Strohmeier, Gernot, Pichler, Harald, Forsyth, V Trevor, Noack, Stephan, Goulding, Celia W, McFadden, Johnjoe, Beste, Dany J V
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094261/
https://www.ncbi.nlm.nih.gov/pubmed/33943004
http://dx.doi.org/10.15252/msb.202110280
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author Borah, Khushboo
Mendum, Tom A
Hawkins, Nathaniel D
Ward, Jane L
Beale, Michael H
Larrouy‐Maumus, Gerald
Bhatt, Apoorva
Moulin, Martine
Haertlein, Michael
Strohmeier, Gernot
Pichler, Harald
Forsyth, V Trevor
Noack, Stephan
Goulding, Celia W
McFadden, Johnjoe
Beste, Dany J V
author_facet Borah, Khushboo
Mendum, Tom A
Hawkins, Nathaniel D
Ward, Jane L
Beale, Michael H
Larrouy‐Maumus, Gerald
Bhatt, Apoorva
Moulin, Martine
Haertlein, Michael
Strohmeier, Gernot
Pichler, Harald
Forsyth, V Trevor
Noack, Stephan
Goulding, Celia W
McFadden, Johnjoe
Beste, Dany J V
author_sort Borah, Khushboo
collection PubMed
description 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.
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spelling pubmed-80942612021-05-14 Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis Borah, Khushboo Mendum, Tom A Hawkins, Nathaniel D Ward, Jane L Beale, Michael H Larrouy‐Maumus, Gerald Bhatt, Apoorva Moulin, Martine Haertlein, Michael Strohmeier, Gernot Pichler, Harald Forsyth, V Trevor Noack, Stephan Goulding, Celia W McFadden, Johnjoe Beste, Dany J V Mol Syst Biol Articles 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. John Wiley and Sons Inc. 2021-05-04 /pmc/articles/PMC8094261/ /pubmed/33943004 http://dx.doi.org/10.15252/msb.202110280 Text en © 2021 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Borah, Khushboo
Mendum, Tom A
Hawkins, Nathaniel D
Ward, Jane L
Beale, Michael H
Larrouy‐Maumus, Gerald
Bhatt, Apoorva
Moulin, Martine
Haertlein, Michael
Strohmeier, Gernot
Pichler, Harald
Forsyth, V Trevor
Noack, Stephan
Goulding, Celia W
McFadden, Johnjoe
Beste, Dany J V
Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis
title Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis
title_full Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis
title_fullStr Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis
title_full_unstemmed Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis
title_short Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis
title_sort metabolic fluxes for nutritional flexibility of mycobacterium tuberculosis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094261/
https://www.ncbi.nlm.nih.gov/pubmed/33943004
http://dx.doi.org/10.15252/msb.202110280
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