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Metabolic anticipation in Mycobacterium tuberculosis


Humans serve as both host and reservoir for Mycobacterium tuberculosis, making tuberculosis a theoretically eradicable disease. How M. tuberculosis alternates between host-imposed quiescence and sporadic bouts of replication to complete its life cycle, however, remains unknown. Here, we identify a metabolic adaptation that is triggered upon entry into hypoxia-induced quiescence but facilitates subsequent cell cycle re-entry. Catabolic remodelling of the cell surface trehalose mycolates of M. tuberculosis specifically generates metabolic intermediates reserved for re-initiation of peptidoglycan biosynthesis. These adaptations reveal a metabolic network with the regulatory capacity to mount an anticipatory response.

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Figure 1: Hypoxia induces remodelling of upper glycolysis, amino sugar and nucleotide sugar biosynthesis and pentose phosphate pathways in M. tuberculosis.
Figure 2: Hypoxia induces selective alterations in M. tuberculosis cell envelope lipid levels and immunoreactivity.
Figure 3: Biochemical essentiality of TreS in hypoxia-triggered anticipatory metabolic remodelling of M. tuberculosis.
Figure 4: Biochemical shunting of hypoxia-induced metabolic stores into de novo peptidoglycan biosynthesis during re-aeration.


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The authors thank G. Rehren and D. Schnappinger for advice in constructing knockout strains, C. Nathan, J. Vaubourgeix, S. Ehrt and S. Tavazoie for critical discussions and reading of the manuscript, S. Fischer for expert mass spectrometric support and the Bill and Melinda Gates Foundation Grand Challenges Exploration Program (OPP1068025) and National Institutes of Health Tri-I TBRU (U19-AI11143) for support.

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Authors and Affiliations



H.E. and Z.W. designed, conducted and analysed metabolomic profiling studies. E.L. and D.B.M. conducted and analysed lipidomic profiling studies. H.E. and P.R. conducted macrophage cytokine release assays. H.E., Z.W. and R.M. conducted antibiotic susceptibility assays. K.Y.R. initiated and directed this research.

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Correspondence to Kyu Y. Rhee.

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The authors declare no competing financial interests.

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Supplementary Information

Supplementary Figures 1–8. (PDF 1539 kb)

Supplementary Data 1

All relevant source data related to metabolomic and lipidomic data shown in Figures 1–4 and Supplementary Figures 1–8. (XLSX 103 kb)

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Eoh, H., Wang, Z., Layre, E. et al. Metabolic anticipation in Mycobacterium tuberculosis. Nat Microbiol 2, 17084 (2017).

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