Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Tuberculosis — metabolism and respiration in the absence of growth

Nature Reviews Microbiology volume 3, pages 70–80 (2005)Cite this article

Key Points

  • Pulmonary tuberculosis is a complex disease that is clinically manifested by the appearance of different types of granulomas including necrotic, caseous and liquefied lesions. Latent bacteria might be responsible for reactivation disease and are thought to reside in caseous granulomas.

  • Several animal models have been used to investigate different aspects of human latent disease. So far, the non-human primate model has shown the most similarity to the heterogeneity of human pulmonary tuberculosis and the development of latent disease.

  • The most thoroughly investigated in vitro model of latent persistence involves a hypoxic culture that is generated by gradual consumption of all the available oxygen in stirred, sealed tubes. Adaptation to hypoxic conditions is associated with the increased expression of several enzymes including nitrate reductase and glycine dehydrogenase.

  • The signal for entry into a state of metabolic persistence may be different in humans and mice. In mice, the metabolic signal is probably provided by nitric oxide. In vitro models have shown that exposure to nitric oxide induces the transcription of a 48-gene regulon in Mycobacterium tuberculosis — the dormancy regulon — and the same regulon is upregulated in infected mice. Nitric oxide exposure shares many transcriptional similarities with hypoxia, but there are some important differences. Low concentrations of oxygen might be the predominant signal for the bacteria during the development of latency in humans.

  • β-oxidation and gluconeogenesis are important for persistence of this pathogen in murine tissues. However, β-oxidation is unlikely to allow M. tuberculosis to maintain redox balance in the absence of external electron acceptors. It is possible that human caseous granulomas that harbour latent organisms are hypoxic, which might indicate that unless these lesions contain sufficient concentrations of nitrate as terminal electron acceptor, fatty acids may not be important during persistence in humans.

  • M. tuberculosis may maintain an energized membrane by fermentation pathways. Transcriptional profiling of anaerobic cultures has revealed that transcription of a set of genes that might have a role in fermentation is induced under such conditions.

Abstract

Human tuberculosis is a complex disease caused by bacterial populations that are located in discrete lesions (microenvironments) in a single host. Some of these microenvironments are conducive to replication, whereas others restrict bacterial growth without necessarily sterilizing the infecting microorganisms. The physical and biochemical milieu in these lesions is poorly defined. None of the existing animal models for tuberculosis (except perhaps non-human primates) reproduce the diversity of disease progression that is seen in humans. Nonetheless, transcriptomics and studies using bacterial mutants have led to testable hypotheses about metabolic functions that are essential for viability in the absence of replication. A complete picture of bacterial metabolism must balance reducing equivalents while maintaining an energized membrane and basic cellular processes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Human granulomas are different from mouse granulomas.
Figure 2: Growth of Mycobacterium tuberculosis in vitro is dependent on oxygen.
Figure 3: Microaerophilic respiration in Mycobacterium tuberculosis showing components of the electron-transport chain and ATP synthase.
Figure 4: The proposed route for regeneration of reducing equivalents is dependent on the availability of terminal electron acceptors.
Figure 5: Proposed pathways that use and regenerate reducing equivalents in the absence of external electron acceptors.

Similar content being viewed by others

References

  1. Corbett, E. L. et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch. Intern. Med. 163, 1009–1021 (2003).

    Article  PubMed  Google Scholar 

  2. Jagirdar, J. & Zagzag, D. in Tuberculosis (eds Rom, W. N. & Garay, S. M.) 323–344 (Lippincott Williams & Wilkins, Philadelphia, 2004). A good current and historical overview of the pathology of different forms of tuberculosis in humans.

    Google Scholar 

  3. Bates, J. H. in The Mycobacteria: A Sourcebook (eds Kubica, G. P. & Wayne, L. G.) 991–1005 (Marcel Dekker, New York, 1984).

    Google Scholar 

  4. Daley, C. L. in Tuberculosis (eds Rom, W. N. & Garay, S. M.) 85–99 (Lippincott Williams & Wilkins, Philadelphia, 2004).

    Google Scholar 

  5. Condos, R. & Rom, W. N. in Tuberculosis (eds Rom, W. N. & Garay, S. M.) 285–299 (Lippincott Williams & Wilkins, Philadelphia, 2004).

    Google Scholar 

  6. Vandiviere, H. M., Loring, W. E., Melvin, I. & Willis, S. The treated pulmonary lesion and its tubercle bacillus. II. The death and resurrection. Am. J. Med. Sci. 232, 30–37 (1956).

    Article  CAS  PubMed  Google Scholar 

  7. Kennedy, H. E., Vandiviere, H. M., Melvin, I. G. & Willis, H. S. The treated pulmonary lesion and its tubercle bacillus. III. Drug susceptibility studies. Am. J. Med. Sci. 233, 676–684 (1957).

    Article  CAS  PubMed  Google Scholar 

  8. Kennedy, H. E., Vandiviere, H. M. & Willis, H. S. The effects of extended incubation on propagability of tubercle bacilli. Am. Rev. Tuberc. 77, 802–814 (1958).

    CAS  PubMed  Google Scholar 

  9. Kaplan, G. et al. Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity. Infect. Immun. 71, 7099–7108 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dannenberg, A. M. Pathogenesis of pulmonary Mycobacterium bovis infection: basic principles established by the rabbit model. Tuberculosis (Edinb.) 81, 87–96 (2001).

    Article  Google Scholar 

  11. Canetti, G. Present aspects of bacterial resistance in tuberculosis. Am. Rev. Respir. Dis. 92, 687–703 (1965).

    CAS  PubMed  Google Scholar 

  12. Lillebaek, T. et al. Stability of DNA patterns and evidence of Mycobacterium tuberculosis reactivation occurring decades after the initial infection. J. Infect. Dis. 188, 1032–1039 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Garay, S. M. in Tuberculosis (eds Rom, W. N. & Garay, S. M.) 345–394 (Lippincott Williams & Wilkins, Philadelphia, 2004). A review of the clinical aspects of pulmonary tuberculosis with well-documented case studies of reactivation disease.

    Google Scholar 

  14. Capuano, S. V. et al. Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection. Infect. Immun. 71, 5831–5844 (2003). Elegantly demonstrates how tuberculosis in non-human primates recapitulates many features of the human disease, including the development of latent disease in a subset of the infected animals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McMurray, D. N., Collins, F. M., Dannenberg, A. M. & Smith, D. W. Pathogenesis of experimental tuberculosis in animal models. Curr. Top. Microbiol. Immunol. 215, 157–179 (1996).

    CAS  PubMed  Google Scholar 

  16. Chan, J., Tanaka, K., Carroll, D., Flynn, J. & Bloom, B. R. Effects of nitric oxide synthase inhibitors on murine infection with Mycobacterium tuberculosis. Infect. Immun. 63, 736–740 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. MacMicking, J. D. et al. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc. Natl Acad. Sci. USA 94, 5243–5248 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Flynn, J. L., Scanga, C. A., Tanaka, K. E. & Chan, J. Effects of aminoguanidine on latent murine tuberculosis. J. Immunol. 160, 1796–1803 (1998).

    CAS  PubMed  Google Scholar 

  19. Scanga, C. A. et al. Reactivation of latent tuberculosis: variations on the Cornell murine model. Infect. Immun. 67, 4531–4538 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. McCune, R. M., McDermott, W. & Tompsett, R. The fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. II. The conversion of tuberculous infection to the latent state by the administration of pyrazinamide and a companion drug. J. Exp. Med. 104, 763–802 (1956).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. McCune, R. M. & Tompsett, R. Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. I. The persistence of drug-susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy. J. Exp. Med. 104, 737–762 (1956).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. de Wit, D., Wootton, M., Dhillon, J. & Mitchison, D. A. The bacterial DNA content of mouse organs in the Cornell model of dormant tuberculosis. Tuber. Lung Dis. 76, 555–562 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Garnier, T. et al. The complete genome sequence of Mycobacterium bovis. Proc. Natl Acad. Sci. USA 100, 7877–7882 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fuller, C. L., Flynn, J. L. & Reinhart, T. A. In situ study of abundant expression of proinflammatory chemokines and cytokines in pulmonary granulomas that develop in cynomolgus macaques experimentally infected with Mycobacterium tuberculosis. Infect. Immun. 71, 7023–7034 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Walsh, G. P. et al. The Philippine cynomolgus monkey (Macaca fasicularis) provides a new nonhuman primate model of tuberculosis that resembles human disease. Nature Med. 2, 430–436 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Langermans, J. A. et al. Divergent effect of bacillus Calmette–Guérin (BCG) vaccination on Mycobacterium tuberculosis infection in highly related macaque species: implications for primate models in tuberculosis vaccine research. Proc. Natl Acad. Sci. USA 98, 11497–11502 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wayne, L. G. & Hayes, L. G. An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infect. Immun. 64, 2062–2069 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wayne, L. G. & Sohaskey, C. D. Nonreplicating persistence of Mycobacterium tuberculosis. Annu. Rev. Microbiol. 55, 139–163 (2001). This excellent review describes the in vitro model for non-replicating persistence based on gradual oxygen depletion of growing cultures. It describes the metabolic changes that have been observed during the hypoxic adaptation period and the initial stages of anaerobic survival.

    Article  CAS  PubMed  Google Scholar 

  29. Wayne, L. G. & Hayes, L. G. Nitrate reduction as a marker for hypoxic shiftdown of Mycobacterium tuberculosis. Tuber. Lung Dis. 79, 127–132 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Muttucumaru, D. G., Roberts, G., Hinds, J., Stabler, R. A. & Parish, T. Gene expression profile of Mycobacterium tuberculosis in a non-replicating state. Tuberculosis (Edinb) 84, 239–246 (2004).

    Article  Google Scholar 

  31. Sohaskey, C. D. & Wayne, L. G. Role of narK2X and narGHJ in hypoxic upregulation of nitrate reduction by Mycobacterium tuberculosis. J. Bacteriol. 185, 7247–7256 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Boshoff, H. I. et al. The transcriptional responses of M. tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J. Biol. Chem. 279, 40174–40184 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Sherman, D. R. et al. Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding α-crystallin. Proc. Natl Acad. Sci. USA 98, 7534–7539 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dawes, S. S. et al. Ribonucleotide reduction in Mycobacterium tuberculosis: function and expression of genes encoding class Ib and class II ribonucleotide reductases. Infect. Immun. 71, 6124–6131 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Durbach, S. I. et al. DNA alkylation damage as a sensor of nitrosative stress in Mycobacterium tuberculosis. Infect. Immun. 71, 997–1000 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Boshoff, H. I., Reed, M. B., Barry, C. E., 3rd & Mizrahi, V. DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis. Cell 113, 183–193 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Tsolaki, A. G. et al. Functional and evolutionary genomics of Mycobacterium tuberculosis: insights from genomic deletions in 100 strains. Proc. Natl Acad. Sci. USA 101, 4865–4870 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hirsh, A. E., Tsolaki, A. G., DeRiemer, K., Feldman, M. W. & Small, P. M. Stable association between strains of Mycobacterium tuberculosis and their human host populations. Proc. Natl Acad. Sci. USA 101, 4871–4876 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Daniel, J. et al. Induction of a novel class of diacylglycerol acyltransferases and triacylglycerol accumulation in Mycobacterium tuberculosis as it goes into a dormancy-like state in culture. J. Bacteriol. 186, 5017–5030 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Betts, J. C., Lukey, P. T., Robb, L. C., McAdam, R. A. & Duncan, K. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol. Microbiol. 43, 717–731 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Dahl, J. L. et al. The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice. Proc. Natl Acad. Sci. USA 100, 10026–10031 (2003). Shows that the stringent response is required for chronic persistence of M. tuberculosis in mice and investigates the possible molecular mechanisms of attenuation using transcriptional profiling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hampshire, T. et al. Stationary phase gene expression of Mycobacterium tuberculosis following a progressive nutrient depletion: a model for persistent organisms? Tuberculosis (Edinb) 84, 228–238 (2004).

    Article  Google Scholar 

  43. Voskuil, M. I., Visconti, K. C. & Schoolnik, G. K. Mycobacterium tuberculosis gene expression during adaptation to stationary phase and low-oxygen dormancy. Tuberculosis (Edinb) 84, 218–227 (2004).

    Article  CAS  Google Scholar 

  44. Kornberg, A., Rao, N. N. & Ault-Riche, D. Inorganic polyphosphate: a molecule of many functions. Annu. Rev. Biochem. 68, 89–125 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Hu, Y., Coates, A. R. & Mitchison, D. A. Sterilizing activities of fluoroquinolones against rifampin-tolerant populations of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 47, 653–657 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hu, Y. et al. Detection of mRNA transcripts and active transcription in persistent Mycobacterium tuberculosis induced by exposure to rifampin or pyrazinamide. J. Bacteriol. 182, 6358–6365 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mitchison, D. A. The search for new sterilizing anti-tuberculosis drugs. Front. Biosci. 9, 1059–1072 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Hondalus, M. K. et al. Attenuation of and protection induced by a leucine auxotroph of Mycobacterium tuberculosis. Infect. Immun. 68, 2888–2898 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Smith, D. A., Parish, T., Stoker, N. G. & Bancroft, G. J. Characterization of auxotrophic mutants of Mycobacterium tuberculosis and their potential as vaccine candidates. Infect. Immun. 69, 1142–1150 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pavelka, M. S., Chen, B., Kelley, C. L., Collins, F. M. & Jacobs W. R. Vaccine efficacy of a lysine auxotroph of Mycobacterium tuberculosis. Infect. Immun. 71, 4190–4192 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jackson, M. et al. Persistence and protective efficacy of a Mycobacterium tuberculosis auxotroph vaccine. Infect. Immun. 67, 2867–2873 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sambandamurthy, V. K. et al. A pantothenate auxotroph of Mycobacterium tuberculosis is highly attenuated and protects mice against tuberculosis. Nature Med. 8, 1171–1174 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. De Voss, J. J. et al. The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc. Natl Acad. Sci. USA 97, 1252–1257 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. McKinney, J. D. et al. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406, 735–738 (2000). Provided one of the first insights into the metabolism of M. tuberculosis during persistence in vivo by showing that a mutation in the isocitrate lyase gene impairs the survival of M. tuberculosis in chronically, but not acutely, infected mice.

    Article  CAS  PubMed  Google Scholar 

  55. Darwin, K. H., Ehrt, S., Gutierrez-Ramos, J. C., Weich, N. & Nathan, C. F. The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science 302, 1963–1966 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Voskuil, M. I. et al. Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J. Exp. Med. 198, 705–713 (2003). Identified the 48-gene dormancy regulon of M. tuberculosis , showed how nitric oxide and oxygen modulate its expression and provided evidence for the role of this regulon in infection in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Nathan, C. & Shiloh, M. U. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc. Natl Acad. Sci. USA 97, 8841–8848 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Roberts, D. M., Liao, R. P., Wisedchaisri, G., Hol, W. G. & Sherman, D. R. Two sensor kinases contribute to the hypoxic response of Mycobacterium tuberculosis. J. Biol. Chem. 279, 23082–23087 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Schnappinger, D. et al. Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment. J. Exp. Med. 198, 693–704 (2003). Provided the first detailed comparison of the transcriptional changes that occur during infection of activated or resting macrophages by M. tuberculosis , as well as the effects of intraphagosomal reactive nitrogen species on bacterial gene transcription, and discusses the implications for bacterial metabolism under these conditions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kana, B. D. et al. Characterization of the cydAB-encoded cytochrome bd oxidase from Mycobacterium smegmatis. J. Bacteriol. 183, 7076–7086 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Poole, R. K. & Cook, G. M. Redundancy of aerobic respiratory chains in bacteria? Routes, reasons and regulation. Adv. Microb. Physiol. 43, 165–224 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Wayne, L. G. & Sramek, H. A. Metronidazole is bactericidal to dormant cells of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 38, 2054–2058 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Brooks, J. V., Furney, S. K. & Orme, I. M. Metronidazole therapy in mice infected with tuberculosis. Antimicrob. Agents Chemother. 43, 1285–1288 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Dhillon, J., Allen, B. W., Hu, Y. M., Coates, A. R. & Mitchison, D. A. Metronidazole has no antibacterial effect in Cornell model murine tuberculosis. Int. J. Tuberc. Lung Dis. 2, 736–742 (1998).

    CAS  PubMed  Google Scholar 

  65. Desai, C. R. et al. Role of metronidazole in improving response and specific drug sensitivity in advanced pulmonary tuberculosis. J. Assoc. Physicians India 37, 694–697 (1989).

    CAS  PubMed  Google Scholar 

  66. Boon, C. & Dick, T. Mycobacterium bovis BCG response regulator essential for hypoxic dormancy. J. Bacteriol. 184, 6760–6767 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Parish, T. et al. Deletion of two-component regulatory systems increases the virulence of Mycobacterium tuberculosis. Infect. Immun. 71, 1134–1140 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Malhotra, V. et al. Disruption of response regulator gene, devR, leads to attenuation in virulence of Mycobacterium tuberculosis. FEMS Microbiol. Lett. 231, 237–245 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Brown, J. M. & Wilson, W. R. Exploiting tumour hypoxia in cancer treatment. Nature Rev. Cancer 4, 437–447 (2004).

    Article  CAS  Google Scholar 

  70. Fenhalls, G. et al. In situ detection of Mycobacterium tuberculosis transcripts in human lung granulomas reveals differential gene expression in necrotic lesions. Infect. Immun. 70, 6330–6338 (2002). Shows how the expression of selected genes that are hypothesized to be important for survival of M. tuberculosis in humans is variable, dependent on the type of lesion and distance from the centre of necrotic granulomas.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Primm, T. P. et al. The stringent response of Mycobacterium tuberculosis is required for long-term survival. J. Bacteriol. 182, 4889–4898 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lorenz, M. C. & Fink, G. R. Life and death in a macrophage: role of the glyoxylate cycle in virulence. Eukaryot. Cell 1, 657–662 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Prigneau, O. et al. Genes involved in β-oxidation, energy metabolism and glyoxylate cycle are induced by Candida albicans during macrophage infection. Yeast 20, 723–730 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Timm, J. et al. Differential expression of iron-, carbon-, and oxygen-responsive mycobacterial genes in the lungs of chronically infected mice and tuberculosis patients. Proc. Natl Acad. Sci. USA 100, 14321–14326 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Fritz, C., Maass, S., Kreft, A. & Bange, F. C. Dependence of Mycobacterium bovis BCG on anaerobic nitrate reductase for persistence is tissue specific. Infect. Immun. 70, 286–291 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Weber, I., Fritz, C., Ruttkowski, S., Kreft, A. & Bange, F. C. Anaerobic nitrate reductase (narGHJI) activity of Mycobacterium bovis BCG in vitro and its contribution to virulence in immunodeficient mice. Mol. Microbiol. 35, 1017–1025 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Nakano, M. M. & Zuber, P. Anaerobic growth of a 'strict aerobe' (Bacillus subtilis). Annu. Rev. Microbiol. 52, 165–190 (1998).

    Article  CAS  PubMed  Google Scholar 

  78. Eschbach, M. et al. Long-term anaerobic survival of the opportunistic pathogen Pseudomonas aeruginosa via pyruvate fermentation. J. Bacteriol. 186, 4596–4604 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. van Hellemond, J. J., van der Klei, A., van Weelden, S. W. & Tielens, A. G. Biochemical and evolutionary aspects of anaerobically functioning mitochondria. Philos. Trans. R. Soc. Lond. B Biol. Sci. 358, 205–213.

  80. Bacon, J. et al. The influence of reduced oxygen availability on pathogenicity and gene expression in Mycobacterium tuberculosis. Tuberculosis (Edinb) 84, 205–217 (2004).

    Article  Google Scholar 

  81. Ragsdale, S. W. Pyruvate ferredoxin oxidoreductase and its radical intermediate. Chem. Rev. 103, 2333–4236 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. King, G. M. Uptake of carbon monoxide and hydrogen at environmentally relevant concentrations by mycobacteria. Appl. Environ. Microbiol. 69, 7266–7272 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Nanba, H., Takaoka, Y. & Hasegawa, J. Purification and characterization of formate dehydrogenase from Ancylobacter aquaticus strain KNK607M, and cloning of the gene. Biosci. Biotechnol. Biochem. 67, 720–728 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Park, H. D. et al. Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis. Mol. Microbiol. 48, 833–843 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Purwantini, E., Gillis, T. P. & Daniels, L. Presence of F420-dependent glucose-6-phosphate dehydrogenase in Mycobacterium and Nocardia species, but absence from Streptomyces and Corynebacterium species and methanogenic Archaea. FEMS Microbiol. Lett. 146, 129–134 (1997).

    Article  CAS  PubMed  Google Scholar 

  86. Deppenmeier, U. The membrane-bound electron transport system of Methanosarcina species. J. Bioenerg. Biomembr. 36, 55–64 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Bruggemann, H., Falinski, F. & Deppenmeier, U. Structure of the F420H2:quinone oxidoreductase of Archaeoglobus fulgidus identification and overproduction of the F420H2-oxidizing subunit. Eur. J. Biochem. 267, 5810–5814 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Cole, S. T. et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Sassetti, C. M., Boyd, D. H. & Rubin, E. J. Genes required for mycobacterial growth defined by high-density mutagenesis. Mol. Microbiol. 48, 77–84 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Stover, C. K. et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405, 962–966 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Via and T.-G. Oh for photographs of lung histopathology and U. Manjunatha for stimulating F420 discussions. We gratefully acknowledge the assistance of B. Doan with figures 3 and 4.

Author information

Authors and Affiliations

  1. Tuberculosis Research Section, LIG/NIAID/NIH, Twinbrook II, Room 239, 12441 Parklawn Drive, Rockville, 20852, Maryland, USA

    Helena I. M. Boshoff & Clifton E. Barry 3rd

Authors
  1. Helena I. M. Boshoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clifton E. Barry 3rd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Helena I. M. Boshoff or Clifton E. Barry 3rd.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez

Mycobacterium bovis

Mycobacterium tuberculosis

Infectious Disease Information

Tuberculosis

FURTHER INFORMATION

Clifton E. Barry's laboratory

Glossary

GHON COMPLEX

The primary lesion together with the draining and affected lymph nodes caused by initial infection by Mycobacterium tuberculosis.

CASEUM

The wet/semi-dry chalky paste that results from tissue necrosis in granulomas.

REACTIVE NITROGEN INTERMEDIATES

Oxides of nitrogen besides nitrite and nitrate that arise in cellular environments, including nitroxyl (NO2•) and nitrosonium ions (NO+), S-nitrosothiols (RSNO), nitric oxide (NO) and peroxynitrites (ONOO−).

REACTIVE OXYGEN INTERMEDIATES

The different oxidation states of oxygen in biological reactions that include hydrogen peroxide (H2O2), superoxide ([O2−]•), singlet oxygen (1O2•), ozone (O3), hydroxyl radical (•OH) and hypohalites (for example, ClO−).

CLUSTERED STRAINS

Isolates of M. tuberculosis obtained from different patients during a defined time period that share sufficient genotypic characteristics so that one can reasonably infer that the patients were infected from each other or a common source.

FERMENTATION

The metabolic process by which energy is derived from substrate-level phosphorylation by the partial oxidation of organic substrates using organic metabolic intermediates as electron donors and electron acceptors.

STRINGENT RESPONSE

The bacterial stress response triggered typically by nutritional starvation which leads to global metabolic and transcriptional changes, the most characteristic being the loss of stable RNA accumulation (tRNA and rRNA) and downregulation of protein synthesis. The stringent response is mediated by intracellular accumulation of phosphorylated derivatives of GTP or GDP, collectively termed (p)ppGpp.

ACID-FAST BACTERIA

Have cell wall characteristics that result in bacilli retaining the red dye carbol fuchsin after an acid wash.

REDOX BALANCE

This refers to the metabolic reactions that are possible or necessary to maintain the NADH:NAD+ ratio in a cell. The number of reactions that generate NADH (or another reduced cofactor such as FADH2) must be balanced by metabolic reactions that reoxidize an equivalent amount of the reduced cofactor.

DISPROPORTIONATION

An oxidation–reduction reaction in which the same molecule is both oxidized and reduced.

MIDPOINT POTENTIAL

The redox potential of a chemical species at which half of the molecules are reduced and half are oxidized. It measures the tendency to oxidize another compound and is measured relative to hydrogen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boshoff, H., Barry, C. Tuberculosis — metabolism and respiration in the absence of growth. Nat Rev Microbiol 3, 70–80 (2005). https://doi.org/10.1038/nrmicro1065

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro1065

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing