1887

Abstract

(Mtb) owes its success as a pathogen in large measure to its ability to exist in a persistent state of ‘dormancy’ resulting in a lifelong latent tuberculosis (TB) infection. An understanding of bacterial adaptation during dormancy will help in devising approaches to counter latent TB infection. models have provided valuable insights into bacterial adaptation; however, they have limitations because they do not disclose the bacterial response to the intracellular environment wherein the bacteria are simultaneously exposed to multiple stresses. We describe the pleiotropic response of Mtb in the vitamin C (vit C) model of dormancy developed in our laboratory. Vit C mediates a rapid regulation of genes representing ~14 % of the genome in Mtb cultures. The upregulated genes were better represented in lipid, intermediary metabolism and regulatory protein categories. The downregulated genes mainly related to virulence, detoxification, information pathways and cell wall processes. A comparison of this response to that in other models indicates that vit C generates a multiple-stress environment for axenic Mtb cultures that resembles a macrophage-like environment. The bacterial response to vit C resembles responses to gaseous stresses such as hypoxia and nitric oxide, oxidative and nitrosative stresses, nutrient starvation and, notably, the activated macrophage environment itself. These responses demonstrate that the influence of vit C on Mtb gene expression extends well beyond the DevR dormancy regulon. A detailed characterization of the response to vit C is expected to disclose useful strategies to counter the adaptive mechanisms essential to Mtb dormancy.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.000049
2015-04-01
2022-01-28
Loading full text...

Full text loading...

/deliver/fulltext/micro/161/4/739.html?itemId=/content/journal/micro/10.1099/mic.0.000049&mimeType=html&fmt=ahah

References

  1. Argüello J. M., Eren E., González-Guerrero M. (2007). The structure and function of heavy metal transport P1B-ATPases. Biometals 20, 233248. [View Article][PubMed] [Google Scholar]
  2. Arruda S., Bomfim G., Knights R., Huima-Byron T., Riley L. W. (1993). Cloning of an M. tuberculosis DNA fragment associated with entry and survival inside cells. Science 261, 14541457. [View Article][PubMed] [Google Scholar]
  3. Barry C. E., Crick D. C., McNeil M. R. (2007). Targeting the formation of the cell wall core of M. tuberculosis . Infect Disord Drug Targets 7, 182202. [View Article][PubMed] [Google Scholar]
  4. Behr M. A., Schroeder B. G., Brinkman J. N., Slayden R. A., Barry C. E. III (2000). A point mutation in the mma3 gene is responsible for impaired methoxymycolic acid production in Mycobacterium bovis BCG strains obtained after 1927. J Bacteriol 182, 33943399. [View Article][PubMed] [Google Scholar]
  5. Betts J. C., Lukey P. T., Robb L. C., McAdam R. A., Duncan K. (2002). Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol 43, 717731. [View Article][PubMed] [Google Scholar]
  6. Biswas T., Tsodikov O. V. (2008). Hexameric ring structure of the N-terminal domain of Mycobacterium tuberculosis DnaB helicase. FEBS J 275, 30643071. [View Article][PubMed] [Google Scholar]
  7. Boshoff H. I., Myers T. G., Copp B. R., McNeil M. R., Wilson M. A., Barry C. E. III (2004). The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J Biol Chem 279, 4017440184. [View Article][PubMed] [Google Scholar]
  8. Bryk R., Lima C. D., Erdjument-Bromage H., Tempst P., Nathan C. (2002). Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science 295, 10731077. [View Article][PubMed] [Google Scholar]
  9. Casali N., White A. M., Riley L. W. (2006). Regulation of the Mycobacterium tuberculosis mce1 operon. J Bacteriol 188, 441449. [View Article][PubMed] [Google Scholar]
  10. Chauhan S., Tyagi J. S. (2008). Cooperative binding of phosphorylated DevR to upstream sites is necessary and sufficient for activation of the Rv3134c-devRS operon in Mycobacterium tuberculosis: implication in the induction of DevR target genes. J Bacteriol 190, 43014312. [View Article][PubMed] [Google Scholar]
  11. Chauhan A., Madiraju M. V., Fol M., Lofton H., Maloney E., Reynolds R., Rajagopalan M. (2006). Mycobacterium tuberculosis cells growing in macrophages are filamentous and deficient in FtsZ rings. J Bacteriol 188, 18561865. [View Article][PubMed] [Google Scholar]
  12. De Majumdar S. D., Vashist A., Dhingra S., Gupta R., Singh A., Challu V. K., Ramanathan V. D., Kumar P., Tyagi J. S. (2012). Appropriate DevR (DosR)-mediated signaling determines transcriptional response, hypoxic viability and virulence of Mycobacterium tuberculosis . PLoS ONE 7, e35847. [View Article][PubMed] [Google Scholar]
  13. Deb C., Lee C. M., Dubey V. S., Daniel J., Abomoelak B., Sirakova T. D., Pawar S., Rogers L., Kolattukudy P. E. (2009). A novel in vitro multiple-stress dormancy model for Mycobacterium tuberculosis generates a lipid-loaded, drug-tolerant, dormant pathogen. PLoS ONE 4, e6077. [View Article][PubMed] [Google Scholar]
  14. Fahey R. C. (2001). Novel thiols of prokaryotes. Annu Rev Microbiol 55, 333356. [View Article][PubMed] [Google Scholar]
  15. Fisher M. A., Plikaytis B. B., Shinnick T. M. (2002). Microarray analysis of the Mycobacterium tuberculosis transcriptional response to the acidic conditions found in phagosomes. J Bacteriol 184, 40254032. [View Article][PubMed] [Google Scholar]
  16. Flesselles B., Anand N. N., Remani J., Loosmore S. M., Klein M. H. (1999). Disruption of the mycobacterial cell entry gene of Mycobacterium bovis BCG results in a mutant that exhibits a reduced invasiveness for epithelial cells. FEMS Microbiol Lett 177, 237242. [View Article][PubMed] [Google Scholar]
  17. Florczyk M. A., McCue L. A., Purkayastha A., Currenti E., Wolin M. J., McDonough K. A. (2003). A family of acr-coregulated Mycobacterium tuberculosis genes shares a common DNA motif and requires Rv3133c (dosR or devR) for expression. Infect Immun 71, 53325343. [View Article][PubMed] [Google Scholar]
  18. Gentle, T. M., Jr & Yeh, M. (1999). Composition for the detection of microorganisms in sample. US Patent 5998517.
  19. Ghodbane R., Raoult D., Drancourt M. (2014). Dramatic reduction of culture time of Mycobacterium tuberculosis . Scient Rep 4, 4236. [View Article][PubMed] [Google Scholar]
  20. Goulding C. W., Bowers P. M., Segelke B., Lekin T., Kim C. Y., Terwilliger T. C., Eisenberg D. (2007). The structure and computational analysis of Mycobacterium tuberculosis protein CitE suggest a novel enzymatic function. J Mol Biol 365, 275283. [View Article][PubMed] [Google Scholar]
  21. Graham J. E., Clark-Curtiss J. E. (1999). Identification of Mycobacterium tuberculosis RNAs synthesized in response to phagocytosis by human macrophages by selective capture of transcribed sequences (SCOTS). Proc Natl Acad Sci U S A 96, 1155411559. [View Article][PubMed] [Google Scholar]
  22. Graña M., Bellinzoni M., Bellalou J., Haouz A., Miras I., Buschiazzo A., Winter N., Alzari P. M. (2010). Crystal structure of Mycobacterium tuberculosis LppA, a lipoprotein confined to pathogenic mycobacteria. Proteins 78, 769772.[PubMed] [Google Scholar]
  23. Hampshire T., Soneji S., Bacon J., James B. W., Hinds J., Laing K., Stabler R. A., Marsh P. D., Butcher P. D. (2004). Stationary phase gene expression of Mycobacterium tuberculosis following a progressive nutrient depletion: a model for persistent organisms?Tuberculosis (Edinb) 84, 228238. [View Article][PubMed] [Google Scholar]
  24. Hemila H., Kaprio J., Pietinen P., Albanes D., Helnonen O. P. (1999). Vitamin C and other compounds in vitamin C rich food in relation to risk of tuberculosis in male smokers. Am J Epidemiol 150, 632641. [View Article][PubMed] [Google Scholar]
  25. Högbom M., Stenmark P., Voevodskaya N., McClarty G., Gräslund A., Nordlund P. (2004). The radical site in chlamydial ribonucleotide reductase defines a new R2 subclass. Science 305, 245248. [View Article][PubMed] [Google Scholar]
  26. Honaker R. W., Dhiman R. K., Narayanasamy P., Crick D. C., Voskuil M. I. (2010). DosS responds to a reduced electron transport system to induce the Mycobacterium tuberculosis DosR regulon. J Bacteriol 192, 64476455. [View Article][PubMed] [Google Scholar]
  27. Hu Y. M., Butcher P. D., Sole K., Mitchison D. A., Coates A. R. (1998). Protein synthesis is shutdown in dormant Mycobacterium tuberculosis and is reversed by oxygen or heat shock. FEMS Microbiol Lett 158, 139145. [View Article][PubMed] [Google Scholar]
  28. Jariwalla R. J., Harakeh S. (1996). Antiviral and immunomodulatory activities of ascorbic acid. Subcell Biochem 25, 213231.[PubMed] [Google Scholar]
  29. Kang C. M., Abbott D. W., Park S. T., Dascher C. C., Cantley L. C., Husson R. N. (2005). The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape. Genes Dev 19, 16921704. [View Article][PubMed] [Google Scholar]
  30. Kumar A., Toledo J. C., Patel R. P., Lancaster J. R. Jr, Steyn A. J. (2007). Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor. Proc Natl Acad Sci U S A 104, 1156811573. [View Article][PubMed] [Google Scholar]
  31. Kumar A., Deshane J. S., Crossman D. K., Bolisetty S., Yan B. S., Kramnik I., Agarwal A., Steyn A. J. (2008). Heme oxygenase-1-derived carbon monoxide induces the Mycobacterium tuberculosis dormancy regulon. J Biol Chem 283, 1803218039. [View Article][PubMed] [Google Scholar]
  32. Loebel R. O., Shorr E., Richardson H. B. (1933). The influence of adverse conditions upon the respiratory metabolism and growth of human tubercle bacilli. J Bacteriol 26, 167200.[PubMed] [Google Scholar]
  33. Malhotra V., Okon B. P., Clark-Curtiss J. E. (2012). Mycobacterium tuberculosis protein kinase K enables growth adaptation through translation control. J Bacteriol 194, 41844196. [View Article][PubMed] [Google Scholar]
  34. Malm S., Tiffert Y., Micklinghoff J., Schultze S., Joost I., Weber I., Horst S., Ackermann B., Schmidt M. et al. (2009). The roles of the nitrate reductase NarGHJI, the nitrite reductase NirBD and the response regulator GlnR in nitrate assimilation of Mycobacterium tuberculosis . Microbiology 155, 13321339. [View Article][PubMed] [Google Scholar]
  35. Mandl J., Szarka A., Bánhegyi G. (2009). Vitamin C: update on physiology and pharmacology. Br J Pharmacol 157, 10971110. [View Article][PubMed] [Google Scholar]
  36. Manganelli R., Voskuil M. I., Schoolnik G. K., Smith I. (2001). The Mycobacterium tuberculosis ECF sigma factor σE: role in global gene expression and survival in macrophages. Mol Microbiol 41, 423437. [View Article][PubMed] [Google Scholar]
  37. Marrero J., Rhee K. Y., Schnappinger D., Pethe K., Ehrt S. (2010). Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection. Proc Natl Acad Sci U S A 107, 98199824. [View Article][PubMed] [Google Scholar]
  38. McConkey M., Smith D. T. (1933). The relation of vitamin C deficiency to intestinal tuberculosis in the guinea pig. J Exp Med 58, 503512. [View Article][PubMed] [Google Scholar]
  39. McKinney J. D., zu Bentrup K. H., Muñoz-Elías E. J., Miczak A., Chen B., Chan W.-T., Swenson D., Sacchettini J. C., Jacobs W. R. Jr, Russell D. G. (2000). Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406, 735738. [View Article][PubMed] [Google Scholar]
  40. Monahan I. M., Mangan J. A., Butcher P. D. (2001). Extraction of RNA from intracellular Mycobacterium tuberculosis: methods, considerations and applications. Methods Molec Med, 54, 3142. [View Article][PubMed] [Google Scholar]
  41. Movahedzadeh F., Smith D. A., Norman R. A., Dinadayala P., Murray-Rust J., Russell D. G., Kendall S. L., Rison S. C., McAlister M. S. et al. (2004). The Mycobacterium tuberculosis ino1 gene is essential for growth and virulence. Mol Microbiol 51, 10031014. [View Article][PubMed] [Google Scholar]
  42. Mulder M. A., Zappe H., Steyn L. M. (1999). The Mycobacterium tuberculosis katG promoter region contains a novel upstream activator. Microbiology 145, 25072518.[PubMed][CrossRef] [Google Scholar]
  43. Muñoz-Elías E. J., McKinney J. D. (2006). Carbon metabolism of intracellular bacteria. Cell Microbiol 8, 1022. [View Article][PubMed] [Google Scholar]
  44. Muñoz-Elías E. J., Timm J., Botha T., Chan W. T., Gomez J. E., McKinney J. D. (2005). Replication dynamics of Mycobacterium tuberculosis in chronically infected mice. Infect Immun 73, 546551. [View Article][PubMed] [Google Scholar]
  45. Muttucumaru D. G., Roberts G., Hinds J., Stabler R. A., Parish T. (2004). Gene expression profile of Mycobacterium tuberculosis in a non-replicating state. Tuberculosis (Edinb) 84, 239246. [View Article][PubMed] [Google Scholar]
  46. Ohno H., Zhu G., Mohan V. P., Chu D., Kohno S., Jacobs W. R. Jr, Chan J. (2003). The effects of reactive nitrogen intermediates on gene expression in Mycobacterium tuberculosis . Cell Microbiol 5, 637648. [View Article][PubMed] [Google Scholar]
  47. Okuyama H., Kankura T., Nojima S. (1967). Positional distribution of fatty acids in phospholipids from mycobacteria. J Biochem 61, 732737.[PubMed] [Google Scholar]
  48. Parish T., Smith D. A., Kendall S., Casali N., Bancroft G. J., Stoker N. G. (2003). Deletion of two-component regulatory systems increases the virulence of Mycobacterium tuberculosis . Infect Immun 71, 11341140. [View Article][PubMed] [Google Scholar]
  49. Park H. D., Guinn K. M., Harrell M. I., Liao R., Voskuil M. I., Tompa M., Schoolnik G. K., Sherman D. R. (2003). Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis . Mol Microbiol 48, 833843. [View Article][PubMed] [Google Scholar]
  50. Pinto R., Tang Q. X., Britton W. J., Leyh T. S., Triccas J. A. (2004). The Mycobacterium tuberculosis cysD and cysNC genes form a stress-induced operon that encodes a tri-functional sulfate-activating complex. Microbiology 150, 16811686. [View Article][PubMed] [Google Scholar]
  51. Raman S., Song T., Puyang X., Bardarov S., Jacobs W. R. Jr, Husson R. N. (2001). The alternative sigma factor SigH regulates major components of oxidative and heat stress responses in Mycobacterium tuberculosis . J Bacteriol 183, 61196125. [View Article][PubMed] [Google Scholar]
  52. Roberts D. M., Liao R. P., Wisedchaisri G., Hol W. G., Sherman D. R. (2004). Two sensor kinases contribute to the hypoxic response of Mycobacterium tuberculosis . J Biol Chem 279, 2308223087. [View Article][PubMed] [Google Scholar]
  53. Rohde K. H., Abramovitch R. B., Russell D. G. (2007). Mycobacterium tuberculosis invasion of macrophages: linking bacterial gene expression to environmental cues. Cell Host Microbe 2, 352364. [View Article][PubMed] [Google Scholar]
  54. Rohde K. H., Veiga D. F. T., Caldwell S., Balázsi G., Russell D. G. (2012). Linking the transcriptional profiles and the physiological states of Mycobacterium tuberculosis during an extended intracellular infection. PLoS Pathog 8, e1002769. [View Article][PubMed] [Google Scholar]
  55. Rowland J. L., Niederweis M. (2012). Resistance mechanisms of Mycobacterium tuberculosis against phagosomal copper overload. Tuberculosis (Edinb) 92, 202210. [View Article][PubMed] [Google Scholar]
  56. Russell D. G. (2011). Mycobacterium tuberculosis and the intimate discourse of a chronic infection. Immunol Rev 240, 252268. [View Article][PubMed] [Google Scholar]
  57. Rustad T. R., Harrell M. I., Liao R., Sherman D. R. (2008). The enduring hypoxic response of Mycobacterium tuberculosis . PLoS ONE 3, e1502. [View Article][PubMed] [Google Scholar]
  58. Saini D. K., Malhotra V., Dey D., Pant N., Das T. K., Tyagi J. S. (2004). DevR–DevS is a bona fide two-component system of Mycobacterium tuberculosis that is hypoxia-responsive in the absence of the DNA-binding domain of DevR. Microbiology 150, 865875. [View Article][PubMed] [Google Scholar]
  59. Sala C., Forti F., Di Florio E., Canneva F., Milano A., Riccardi G., Ghisotti D. (2003). Mycobacterium tuberculosis FurA autoregulates its own expression. J Bacteriol 185, 53575362. [View Article][PubMed] [Google Scholar]
  60. Scarpa M., Stevanato R., Viglino P., Rigo A. (1983). Superoxide ion as active intermediate in the autoxidation of ascorbate by molecular oxygen. Effect of superoxide dismutase. J Biol Chem 258, 66956697.[PubMed] [Google Scholar]
  61. Schnappinger D., Ehrt S., Voskuil M. I., Liu Y., Mangan J. A., Monahan I. M., Dolganov G., Efron B., Butcher P. D. et al. (2003). Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment. J Exp Med 198, 693704. [View Article][PubMed] [Google Scholar]
  62. Sherman D. R., Voskuil M., Schnappinger D., Liao R., Harrell M. I., Schoolnik G. K. (2001). Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding α-crystallin. Proc Natl Acad Sci U S A 98, 75347539. [View Article][PubMed] [Google Scholar]
  63. Sikri K., Tyagi J. S. (2013). The evolution of Mycobacterium tuberculosis dormancy models. Curr Sci 105, 607616. [Google Scholar]
  64. Sohaskey C. D., Wayne L. G. (2003). Role of narK2X and narGHJI in hypoxic upregulation of nitrate reduction by Mycobacterium tuberculosis . J Bacteriol 185, 72477256. [View Article][PubMed] [Google Scholar]
  65. Sousa E. H., Tuckerman J. R., Gonzalez G., Gilles-Gonzalez M. A. (2007). DosT and DevS are oxygen-switched kinases in Mycobacterium tuberculosis . Protein Sci 16, 17081719. [View Article][PubMed] [Google Scholar]
  66. Starck J., Källenius G., Marklund B. I., Andersson D. I., Akerlund T. (2004). Comparative proteome analysis of Mycobacterium tuberculosis grown under aerobic and anaerobic conditions. Microbiology 150, 38213829. [View Article][PubMed] [Google Scholar]
  67. Stewart G. R., Snewin V. A., Walzl G., Hussell T., Tormay P., O’Gaora P., Goyal M., Betts J., Brown I. N., Young D. B. (2001). Overexpression of heat-shock proteins reduces survival of Mycobacterium tuberculosis in the chronic phase of infection. Nat Med 7, 732737. [View Article][PubMed] [Google Scholar]
  68. Stewart G. R., Wernisch L., Stabler R., Mangan J. A., Hinds J., Laing K. G., Young D. B., Butcher P. D. (2002). Dissection of the heat-shock response in Mycobacterium tuberculosis using mutants and microarrays. Microbiology 148, 31293138.[PubMed] [Google Scholar]
  69. Sulzenbacher G., Canaan S., Bordat Y., Neyrolles O., Stadthagen G., Roig-Zamboni V., Rauzier J., Maurin D., Laval F. et al. (2006). LppX is a lipoprotein required for the translocation of phthiocerol dimycocerosates to the surface of Mycobacterium tuberculosis . EMBO J 25, 14361444. [View Article][PubMed] [Google Scholar]
  70. Taneja N. K., Dhingra S., Mittal A., Naresh M., Tyagi J. S. (2010). Mycobacterium tuberculosis transcriptional adaptation, growth arrest and dormancy phenotype development is triggered by vitamin C. PLoS ONE 5, e10860. [View Article][PubMed] [Google Scholar]
  71. Vilchèze C., Hartman T., Weinrick B., Jacobs W. R. Jr (2013). Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction. Nat Commun 4, 1881. [View Article][PubMed] [Google Scholar]
  72. Voskuil M. I., Schnappinger D., Visconti K. C., Harrell M. I., Dolganov G. M., Sherman D. R., Schoolnik G. K. (2003). Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J Exp Med 198, 705713. [View Article][PubMed] [Google Scholar]
  73. Voskuil M. I., Visconti K. C., Schoolnik G. K. (2004). Mycobacterium tuberculosis gene expression during adaptation to stationary phase and low-oxygen dormancy. Tuberculosis (Edinb) 84, 218227. [View Article][PubMed] [Google Scholar]
  74. Voskuil M. I., Bartek I. L., Visconti K., Schoolnik G. K. (2011). The response of Mycobacterium tuberculosis to reactive oxygen and nitrogen species. Front Microbiol 2, 105. [View Article][PubMed] [Google Scholar]
  75. Walker R. W., Barakat H., Hung J. G. (1970). The positional distribution of fatty acids in the phospholipids and triglycerides of Mycobacterium smegmatis and M. bovis BCG. Lipids 5, 684691. [View Article][PubMed] [Google Scholar]
  76. Ward S. K., Abomoelak B., Hoye E. A., Steinberg H., Talaat A. M. (2010). CtpV: a putative copper exporter required for full virulence of Mycobacterium tuberculosis . Mol Microbiol 77, 10961110. [View Article][PubMed] [Google Scholar]
  77. Wayne L. G. (1976). Dynamics of submerged growth of Mycobacterium tuberculosis under aerobic and microaerophilic conditions. Am Rev Respir Dis 114, 807811.[PubMed] [Google Scholar]
  78. Wayne L. G., Diaz G. A. (1967). Autolysis and secondary growth of Mycobacterium tuberculosis in submerged culture. J Bacteriol 93, 13741381.[PubMed] [Google Scholar]
  79. Wayne L. G., Hayes L. G. (1996). An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infect Immun 64, 20622069.[PubMed] [Google Scholar]
  80. Wong D., Bach H., Sun J., Hmama Z., Av-Gay Y. (2011). Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification. Proc Natl Acad Sci U S A 108, 1937119376. [View Article][PubMed] [Google Scholar]
  81. Yamamoto K., Muniruzzaman S., Rajagopalan M., Madiraju M. V. (2002). Modulation of Mycobacterium tuberculosis DnaA protein–adenine-nucleotide interactions by acidic phospholipids. Biochem J 363, 305311. [View Article][PubMed] [Google Scholar]
  82. Yuan Y., Crane D. D., Simpson R. M., Zhu Y. Q., Hickey M. J., Sherman D. R., Barry C. E. III (1998). The 16-kDa α-crystallin (Acr) protein of Mycobacterium tuberculosis is required for growth in macrophages. Proc Natl Acad Sci U S A 95, 95789583. [View Article][PubMed] [Google Scholar]
  83. zu Bentrup K. H., Russell D. G. (2001). Mycobacterial persistence: adaptation to a changing environment. Trends Microbiol 9, 597605. [View Article][PubMed] [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.000049
Loading
/content/journal/micro/10.1099/mic.0.000049
Loading

Data & Media loading...

Supplements

Supplementary Data



PDF

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error