Letter | Published:

Metabolic anticipation in Mycobacterium tuberculosis

Nature Microbiology volume 2, Article number: 17084 (2017) | Download Citation


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.


  1. 1.

    , & Tuberculosis: what we don't know can, and does, hurt us. Science 328, 852–856 (2010).

  2. 2.

    & The equilibria that allow bacterial persistence in human hosts. Nature 449, 843–849 (2007).

  3. 3.

    , , & Hypoxia: a window into Mycobacterium tuberculosis latency. Cell Microbiol. 11, 1151–1159 (2009).

  4. 4.

    et al. Comprehensive physicochemical, pharmacokinetic and activity profiling of anti-TB agents. J. Antimicrob. Chemother. 70, 857–867 (2015).

  5. 5.

    & Tuberculosis chemotherapy: the influence of bacillary stress and damage response pathways on drug efficacy. Clin. Microbiol. Rev. 19, 558–570 (2006).

  6. 6.

    et al. Fumarate reductase activity maintains an energized membrane in anaerobic mycobacterium tuberculosis. PLoS Pathog. 7, e1002287 (2011).

  7. 7.

    & Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 110, 6554–6559 (2013).

  8. 8.

    et al. Mycobacterium tuberculosis Ser/Thr protein kinase B mediates an oxygen-dependent replication switch. PLoS Biol. 12, e1001746 (2014).

  9. 9.

    et al. Systematic survey of serine hydrolase activity in Mycobacterium tuberculosis defines changes associated with persistence. Cell Chem. Biol. 23, 290–298 (2016).

  10. 10.

    et al. Absolute proteome composition and dynamics during dormancy and resuscitation of Mycobacterium tuberculosis. Cell Host Microbe. 18, 96–108 (2015).

  11. 11.

    & Genetics of mycobacterial trehalose metabolism. Microbiol. Spectr. (2014).

  12. 12.

    et al. Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J. Exp. Med. 206, 2879–2888 (2009).

  13. 13.

    et al. The Mycobacterium tuberculosis regulatory network and hypoxia. Nature 499, 178–183 (2013).

  14. 14.

    et al. Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an α-glucan pathway. Nat. Chem. Biol. 6, 376–384 (2010).

  15. 15.

    et al. Flux through trehalose synthase flows from trehalose to the alpha anomer of maltose in mycobacteria. Chem. Biol. 20, 487–493 (2013).

  16. 16.

    et al. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol. Rev. Camb. Philos. Soc. 90, 927–963 (2015)

  17. 17.

    , , & The versatility of phosphoenolpyruvate and its vinyl ether products in biosynthesis. Chem. Biol. 3, 83–91 (1996).

  18. 18.

    et al. Alteration of a single amino acid residue reverses fosfomycin resistance of recombinant MurA from Mycobacterium tuberculosis. Microbiology 145, 3177–3184 (1999).

  19. 19.

    , , & Population diversification in a yeast metabolic program promotes anticipation of environmental shifts. PLoS Biol. 13, e1002042 (2015).

  20. 20.

    et al. Adaptive prediction of environmental changes by microorganisms. Nature 460, 220–224 (2009).

  21. 21.

    , & Predictive behavior within microbial genetic networks. Science 320, 1313–1317 (2008).

  22. 22.

    Mycobacterium tuberculosis metabolism. Cold Spring Harb. Perspect. Med. 5, pii.a021121 (2015).

  23. 23.

    , , , & The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 105, 11945–11950 (2008).

  24. 24.

    et al. A cytoplasmic peptidoglycan amidase homologue controls mycobacterial cell wall synthesis. eLife 5, e14590 (2016).

  25. 25.

    et al. The three Mycobacterium tuberculosis antigen 85 isoforms have unique substrates and activities determined by non-active site regions. J. Biol. Chem. 289, 25041–25053 (2014).

  26. 26.

    et al. Lost in transition: start-up of glycolysis yields subpopulations of nongrowing cells. Science 343, 1245114 (2014).

  27. 27.

    , & Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses. Immunol. Rev. 264, 288–307 (2015).

  28. 28.

    et al. Metabolomics of Mycobacterium tuberculosis reveals compartmentalized co-catabolism of carbon substrates. Chem. Biol. 17, 1122–1131 (2010).

  29. 29.

    et al. A comparative lipidomics platform for chemotaxonomic analysis of Mycobacterium tuberculosis. Chem. Biol. 18, 1537–1549 (2011).

  30. 30.

    et al. Reprogramming of the macrophage transcriptome in response to interferon-γ and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase. J. Exp. Med. 194, 1123–1140 (2001).

Download references


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.

Author information

Author notes

    • Hyungjin Eoh
    •  & Emilie Layre

    Present addresses: Keck School of Medicine, Department of Molecular Microbiology & Immunology, ZNI 537 1501 San Pablo, Los Angeles, California 90033, USA (H.E.); National Center for Scientific Research, Institute of Pharmacology & Structural Biology, 205 route de Narbonne BP64182, Toulouse 31077, France (E.L.).


  1. Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA

    • Hyungjin Eoh
    • , Zhe Wang
    • , Roxanne Morris
    •  & Kyu Y. Rhee
  2. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    • Emilie Layre
    •  & D. Branch Moody
  3. Department of Microbiology & Immunology, Weill Cornell Medical College, New York, New York 10065, USA

    • Poonam Rath
    •  & Kyu Y. Rhee


  1. Search for Hyungjin Eoh in:

  2. Search for Zhe Wang in:

  3. Search for Emilie Layre in:

  4. Search for Poonam Rath in:

  5. Search for Roxanne Morris in:

  6. Search for D. Branch Moody in:

  7. Search for Kyu Y. Rhee in:


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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kyu Y. Rhee.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Figures 1–8.

Excel files

  1. 1.

    Supplementary Data 1

    All relevant source data related to metabolomic and lipidomic data shown in Figures 1–4 and Supplementary Figures 1–8.

About this article

Publication history