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Metabolic anticipation in Mycobacterium tuberculosis

Abstract

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.

References

  1. 1

    Russell, D. G., Barry, C. E. III & Flynn, J. L. Tuberculosis: what we don't know can, and does, hurt us. Science 328, 852–856 (2010).

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Rustad, T. R., Sherrid, A. M., Minch, K. J. & Sherman, D. R. Hypoxia: a window into Mycobacterium tuberculosis latency. Cell Microbiol. 11, 1151–1159 (2009).

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 8

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

    Article  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 11

    Kalscheuer, R. & Koliwer-Brandl, H. Genetics of mycobacterial trehalose metabolism. Microbiol. Spectr. http://dx.doi.org/10.1128/microbiolspec.MGM2-0002-2013 (2014).

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

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

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  15. 15

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

    CAS  Article  Google Scholar 

  16. 16

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

    Article  Google Scholar 

  17. 17

    Walsh, C. T., Benson, T. E., Kim, D. H. & Lees, W. J. The versatility of phosphoenolpyruvate and its vinyl ether products in biosynthesis. Chem. Biol. 3, 83–91 (1996).

    CAS  Article  Google Scholar 

  18. 18

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

    CAS  Article  Google Scholar 

  19. 19

    Venturelli, O. S., Zuleta, I., Murray, R. M. & El-Samad, H. Population diversification in a yeast metabolic program promotes anticipation of environmental shifts. PLoS Biol. 13, e1002042 (2015).

    Article  Google Scholar 

  20. 20

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

    CAS  Article  Google Scholar 

  21. 21

    Tagkopoulos, I., Liu, Y. C. & Tavazoie, S. Predictive behavior within microbial genetic networks. Science 320, 1313–1317 (2008).

    CAS  Article  Google Scholar 

  22. 22

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

    Article  Google Scholar 

  23. 23

    Rao, S. P., Alonso, S., Rand, L., Dick, T. & Pethe, K. 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).

    CAS  Article  Google Scholar 

  24. 24

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

    Article  Google Scholar 

  25. 25

    Backus, K. M. 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).

    CAS  Article  Google Scholar 

  26. 26

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

    Article  Google Scholar 

  27. 27

    Lenaerts, A., Barry, C. E. III & Dartois, V. Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses. Immunol. Rev. 264, 288–307 (2015).

    CAS  Article  Google Scholar 

  28. 28

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

    CAS  Article  Google Scholar 

  29. 29

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

    CAS  Article  Google Scholar 

  30. 30

    Ehrt, S. 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).

    CAS  Article  Google Scholar 

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Acknowledgements

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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Contributions

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.

Corresponding author

Correspondence to Kyu Y. Rhee.

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The authors declare no competing financial interests.

Supplementary information

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). https://doi.org/10.1038/nmicrobiol.2017.84

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