No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

in the Face of Host-Imposed Nutrient Limitation

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • XML
    141.60 Kb
  • PDF
    371.21 Kb
  • HTML
    142.55 Kb
  • Authors: Michael Berney1, Linda Berney-Meyer2
  • Editors: William R. Jacobs Jr.3, Helen McShane4, Valerie Mizrahi5, Ian M. Orme6
    Affiliations: 1: Albert Einstein College of Medicine, Department of Microbiology and Immunology, New York, NY 10461; 2: Albert Einstein College of Medicine, Department of Microbiology and Immunology, New York, NY 10461; 3: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 4: University of Oxford, Oxford OX3 7DQ, United Kingdom; 5: University of Cape Town, Rondebosch 7701, South Africa; 6: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0030-2016
  • Received 15 September 2016 Accepted 31 March 2017 Published 09 June 2017
  • Michael Berney, [email protected]
image of <span class="jp-italic">Mycobacterium tuberculosis</span> in the Face of Host-Imposed Nutrient Limitation
    Preview this microbiology spectrum article:
    Zoom in

    in the Face of Host-Imposed Nutrient Limitation, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/5/3/TBTB2-0030-2016-1.gif /docserver/preview/fulltext/microbiolspec/5/3/TBTB2-0030-2016-2.gif
  • Abstract:

    Coevolution of pathogens and host has led to many metabolic strategies employed by intracellular pathogens to deal with the immune response and the scarcity of food during infection. Simply put, bacterial pathogens are just looking for food. As a consequence, the host has developed strategies to limit nutrients for the bacterium by containment of the intruder in a pathogen-containing vacuole and/or by actively depleting nutrients from the intracellular space, a process called nutritional immunity. Since metabolism is a prerequisite for virulence, such pathways could potentially be good targets for antimicrobial therapies. In this chapter, we review the current knowledge about the diet of , with a focus on amino acid and cofactors, discuss evidence for the bacilli’s nutritionally independent lifestyle in the host, and evaluate strategies for new chemotherapeutic interventions.

  • Citation: Berney M, Berney-Meyer L. 2017. in the Face of Host-Imposed Nutrient Limitation. Microbiol Spectrum 5(3):TBTB2-0030-2016. doi:10.1128/microbiolspec.TBTB2-0030-2016.


1. Chaston J, Goodrich-Blair H. 2010. Common trends in mutualism revealed by model associations between invertebrates and bacteria. FEMS Microbiol Rev 34:41–58 http://dx.doi.org/10.1111/j.1574-6976.2009.00193.x.
2. Cambier CJ, Falkow S, Ramakrishnan L. 2014. Host evasion and exploitation schemes of Mycobacterium tuberculosis. Cell 159:1497–1509 http://dx.doi.org/10.1016/j.cell.2014.11.024.
3. Eisenreich W, Heesemann J, Rudel T, Goebel W. 2013. Metabolic host responses to infection by intracellular bacterial pathogens. Front Cell Infect Microbiol 3:24 http://dx.doi.org/10.3389/fcimb.2013.00024.
4. Zhang YJ, Rubin EJ. 2013. Feast or famine: the host-pathogen battle over amino acids. Cell Microbiol 15:1079–1087 http://dx.doi.org/10.1111/cmi.12140.
5. Appelberg R. 2006. Macrophage nutriprive antimicrobial mechanisms. J Leukoc Biol 79:1117–1128 http://dx.doi.org/10.1189/jlb.0206079.
6. Hood MI, Skaar EP. 2012. Nutritional immunity: transition metals at the pathogen-host interface. Nat Rev Microbiol 10:525–537 http://dx.doi.org/10.1038/nrmicro2836.
7. Zhang YJ, Reddy MC, Ioerger TR, Rothchild AC, Dartois V, Schuster BM, Trauner A, Wallis D, Galaviz S, Huttenhower C, Sacchettini JC, Behar SM, Rubin EJ. 2013. Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing. Cell 155:1296–1308 http://dx.doi.org/10.1016/j.cell.2013.10.045.
8. Barber MF, Elde NC. 2014. Escape from bacterial iron piracy through rapid evolution of transferrin. Science 346:1362–1366 http://dx.doi.org/10.1126/science.1259329.
9. Kehl-Fie TE, Skaar EP. 2010. Nutritional immunity beyond iron: a role for manganese and zinc. Curr Opin Chem Biol 14:218–224 http://dx.doi.org/10.1016/j.cbpa.2009.11.008.
10. MacMicking JD. 2014. Cell-autonomous effector mechanisms against mycobacterium tuberculosis. Cold Spring Harb Perspect Med 4:a018507 http://dx.doi.org/10.1101/cshperspect.a018507.
11. Michelucci A, Cordes T, Ghelfi J, Pailot A, Reiling N, Goldmann O, Binz T, Wegner A, Tallam A, Rausell A, Buttini M, Linster CL, Medina E, Balling R, Hiller K. 2013. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci USA 110:7820–7825 http://dx.doi.org/10.1073/pnas.1218599110.
12. Tattoli I, Sorbara MT, Vuckovic D, Ling A, Soares F, Carneiro LA, Yang C, Emili A, Philpott DJ, Girardin SE. 2012. Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program. Cell Host Microbe 11:563–575 http://dx.doi.org/10.1016/j.chom.2012.04.012.
13. Silva NM, Rodrigues CV, Santoro MM, Reis LF, Alvarez-Leite JI, Gazzinelli RT. 2002. Expression of indoleamine 2,3-dioxygenase, tryptophan degradation, and kynurenine formation during in vivo infection with Toxoplasma gondii: induction by endogenous gamma interferon and requirement of interferon regulatory factor 1. Infect Immun 70:859–868 http://dx.doi.org/10.1128/IAI.70.2.859-868.2002.
14. Fujigaki S, Saito K, Takemura M, Maekawa N, Yamada Y, Wada H, Seishima M. 2002. l-tryptophan- l-kynurenine pathway metabolism accelerated by Toxoplasma gondii infection is abolished in gamma interferon-gene-deficient mice: cross-regulation between inducible nitric oxide synthase and indoleamine-2,3-dioxygenase. Infect Immun 70:779–786 http://dx.doi.org/10.1128/IAI.70.2.779-786.2002.
15. Rottenberg ME, Gigliotti Rothfuchs A, Gigliotti D, Ceausu M, Une C, Levitsky V, Wigzell H. 2000. Regulation and role of IFN-gamma in the innate resistance to infection with Chlamydia pneumoniae. J Immunol 164:4812–4818 http://dx.doi.org/10.4049/jimmunol.164.9.4812.
16. Price CT, Richards AM, Von Dwingelo JE, Samara HA, Abu Kwaik Y. 2014. Amoeba host- Legionella synchronization of amino acid auxotrophy and its role in bacterial adaptation and pathogenic evolution. Environ Microbiol 16:350–358 http://dx.doi.org/10.1111/1462-2920.12290.
17. Meibom KL, Charbit A. 2010. Francisella tularensis metabolism and its relation to virulence. Front Microbiol 1:140 http://dx.doi.org/10.3389/fmicb.2010.00140.
18. Schneebeli R, Egli T. 2013. A defined, glucose-limited mineral medium for the cultivation of Listeria spp. Appl Environ Microbiol 79:2503–2511 http://dx.doi.org/10.1128/AEM.03538-12.
19. Abu Kwaik Y, Bumann D. 2013. Microbial quest for food in vivo: ‘nutritional virulence’ as an emerging paradigm. Cell Microbiol 15:882–890 http://dx.doi.org/10.1111/cmi.12138.
20. Flynn JL, Chan J, Lin PL. 2011. Macrophages and control of granulomatous inflammation in tuberculosis. Mucosal Immunol 4:271–278 http://dx.doi.org/10.1038/mi.2011.14.
21. Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, Parkhill J, Malla B, Berg S, Thwaites G, Yeboah-Manu D, Bothamley G, Mei J, Wei L, Bentley S, Harris SR, Niemann S, Diel R, Aseffa A, Gao Q, Young D, Gagneux S. 2013. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet 45:1176–1182 http://dx.doi.org/10.1038/ng.2744.
22. Cambier CJ, Takaki KK, Larson RP, Hernandez RE, Tobin DM, Urdahl KB, Cosma CL, Ramakrishnan L. 2014. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 505:218–222 http://dx.doi.org/10.1038/nature12799.
23. van der Wel N, Hava D, Houben D, Fluitsma D, van Zon M, Pierson J, Brenner M, Peters PJ. 2007. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129:1287–1298 http://dx.doi.org/10.1016/j.cell.2007.05.059.
24. Davis JM, Ramakrishnan L. 2009. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 136:37–49 http://dx.doi.org/10.1016/j.cell.2008.11.014.
25. Clay H, Davis JM, Beery D, Huttenlocher A, Lyons SE, Ramakrishnan L. 2007. Dichotomous role of the macrophage in early Mycobacterium marinum infection of the zebrafish. Cell Host Microbe 2:29–39 http://dx.doi.org/10.1016/j.chom.2007.06.004.
26. Fortune SM, Rubin EJ. 2007. The complex relationship between mycobacteria and macrophages: it’s not all bliss. Cell Host Microbe 2:5–6 http://dx.doi.org/10.1016/j.chom.2007.06.008.
27. Eisenreich W, Dandekar T, Heesemann J, Goebel W. 2010. Carbon metabolism of intracellular bacterial pathogens and possible links to virulence. Nat Rev Microbiol 8:401–412 http://dx.doi.org/10.1038/nrmicro2351.
28. Fuchs TM, Eisenreich W, Heesemann J, Goebel W. 2012. Metabolic adaptation of human pathogenic and related nonpathogenic bacteria to extra- and intracellular habitats. FEMS Microbiol Rev 36:435–462 http://dx.doi.org/10.1111/j.1574-6976.2011.00301.x.
29. Cheng J, Che N, Li H, Ma K, Wu S, Fang J, Rong Gao JL, Yan X, Fangting CL, Dong F. 2013. Gas chromatography time-of-flight mass-spectrometry-based metabolomic analysis of human macrophages infected by M. tuberculosis. Anal Lett 46:1922–1936 http://dx.doi.org/10.1080/00032719.2013.777924.
30. Beste DJ, Nöh K, Niedenführ S, Mendum TA, Hawkins ND, Ward JL, Beale MH, Wiechert W, McFadden J. 2013. 13C-flux spectral analysis of host-pathogen metabolism reveals a mixed diet for intracellular Mycobacterium tuberculosis. Chem Biol 20:1012–1021 http://dx.doi.org/10.1016/j.chembiol.2013.06.012.
31. Gouzy A, Larrouy-Maumus G, Bottai D, Levillain F, Dumas A, Wallach JB, Caire-Brandli I, de Chastellier C, Wu TD, Poincloux R, Brosch R, Guerquin-Kern JL, Schnappinger D, Sório de Carvalho LP, Poquet Y, Neyrolles O. 2014. Mycobacterium tuberculosis exploits asparagine to assimilate nitrogen and resist acid stress during infection. PLoS Pathog 10:e1003928 http://dx.doi.org/10.1371/journal.ppat.1003928.
32. Gouzy A, Larrouy-Maumus G, Wu TD, Peixoto A, Levillain F, Lugo-Villarino G, Guerquin-Kern JL, de Carvalho LP, Poquet Y, Neyrolles O. 2013. Mycobacterium tuberculosis nitrogen assimilation and host colonization require aspartate. Nat Chem Biol 9:674–676 http://dx.doi.org/10.1038/nchembio.1355.
33. de Carvalho LP, Fischer SM, Marrero J, Nathan C, Ehrt S, Rhee KY. 2010. Metabolomics of Mycobacterium tuberculosis reveals compartmentalized co-catabolism of carbon substrates. Chem Biol 17:1122–1131 http://dx.doi.org/10.1016/j.chembiol.2010.08.009.
34. Noy T, Vergnolle O, Hartman TE, Rhee KY, Jacobs WR Jr, Berney M, Blanchard JS. 2016. Central role of pyruvate kinase in carbon co-catabolism of Mycobacterium tuberculosis. J Biol Chem 291:7060–7069 http://dx.doi.org/10.1074/jbc.M115.707430.
35. Mehrotra P, Jamwal SV, Saquib N, Sinha N, Siddiqui Z, Manivel V, Chatterjee S, Rao KV. 2014. Pathogenicity of Mycobacterium tuberculosis is expressed by regulating metabolic thresholds of the host macrophage. PLoS Pathog 10:e1004265 http://dx.doi.org/10.1371/journal.ppat.1004265.
36. Watrous JD, Dorrestein PC. 2011. Imaging mass spectrometry in microbiology. Nat Rev Microbiol 9:683–694 http://dx.doi.org/10.1038/nrmicro2634.
37. Marakalala MJ, Raju RM, Sharma K, Zhang YJ, Eugenin EA, Prideaux B, Daudelin IB, Chen PY, Booty MG, Kim JH, Eum SY, Via LE, Behar SM, Barry CE III, Mann M, Dartois V, Rubin EJ. 2016. Inflammatory signaling in human tuberculosis granulomas is spatially organized. Nat Med 22:531–538 http://dx.doi.org/10.1038/nm.4073.
38. Prideaux B, Via LE, Zimmerman MD, Eum S, Sarathy J, O’Brien P, Chen C, Kaya F, Weiner DM, Chen PY, Song T, Lee M, Shim TS, Cho JS, Kim W, Cho SN, Olivier KN, Barry CE III, Dartois V. 2015. The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med 21:1223–1227 http://dx.doi.org/10.1038/nm.3937.
39. Fletcher JS, Kotze HL, Armitage EG, Lockyer NP, Vickerman JC. 2013. Evaluating the challenges associated with time-of-flight secondary ion mass spectrometry for metabolomics using pure and mixed metabolites. Metabolomics 9:535–544 http://dx.doi.org/10.1007/s11306-012-0487-4.
40. Shin JH, Yang JY, Jeon BY, Yoon YJ, Cho SN, Kang YH, Ryu DH, Hwang GS. 2011. (1)H NMR-based metabolomic profiling in mice infected with Mycobacterium tuberculosis. J Proteome Res 10:2238–2247. [PubMed]
41. Somashekar BS, Amin AG, Rithner CD, Troudt J, Basaraba R, Izzo A, Crick DC, Chatterjee D. 2011. Metabolic profiling of lung granuloma in Mycobacterium tuberculosis infected guinea pigs: ex vivo 1H magic angle spinning NMR studies. J Proteome Res 10:4186–4195 http://dx.doi.org/10.1021/pr2003352.
42. Lederberg J, Tatum EL. 1953. Sex in bacteria; genetic studies, 1945–1952. Science 118:169–175 http://dx.doi.org/10.1126/science.118.3059.169.
43. Lederberg J, Tatum EL. 1946. Gene recombination in Escherichia coli. Nature 158:558 http://dx.doi.org/10.1038/158558a0.
44. Lederberg J, Tatum EL. 1946. Detection of biochemical mutants of microorganisms. J Biol Chem 165:381. [PubMed]
45. Tatum EL, Lederberg J. 1947. Gene recombination in the bacterium Escherichia coli. J Bacteriol 53:673–684. [PubMed]
46. Davis BD. 1950. Nonfiltrability of the agents of genetic recombination in Escherichia coli. J Bacteriol 60:507–508. [PubMed]
47. McAdam RA, Weisbrod TR, Martin J, Scuderi JD, Brown AM, Cirillo JD, Bloom BR, Jacobs WR Jr. 1995. In vivo growth characteristics of leucine and methionine auxotrophic mutants of Mycobacterium bovis BCG generated by transposon mutagenesis. Infect Immun 63:1004–1012. [PubMed]
48. Parish T, Gordhan BG, McAdam RA, Duncan K, Mizrahi V, Stoker NG. 1999. Production of mutants in amino acid biosynthesis genes of Mycobacterium tuberculosis by homologous recombination. Microbiology 145:3497–3503 http://dx.doi.org/10.1099/00221287-145-12-3497.
49. Hondalus MK, Bardarov S, Russell R, Chan J, Jacobs WR Jr, Bloom BR. 2000. Attenuation of and protection induced by a leucine auxotroph of Mycobacterium tuberculosis. Infect Immun 68:2888–2898 http://dx.doi.org/10.1128/IAI.68.5.2888-2898.2000.
50. Smith DA, Parish T, Stoker NG, Bancroft GJ. 2001. Characterization of auxotrophic mutants of Mycobacterium tuberculosis and their potential as vaccine candidates. Infect Immun 69:1142–1150 http://dx.doi.org/10.1128/IAI.69.2.1442-1150.2001.
51. Woong Park S, Klotzsche M, Wilson DJ, Boshoff HI, Eoh H, Manjunatha U, Blumenthal A, Rhee K, Barry CE III, Aldrich CC, Ehrt S, Schnappinger D. 2011. Evaluating the sensitivity of Mycobacterium tuberculosis to biotin deprivation using regulated gene expression. PLoS Pathog 7:e1002264 http://dx.doi.org/10.1371/journal.ppat.1002264.
52. Dick T, Manjunatha U, Kappes B, Gengenbacher M. 2010. Vitamin B6 biosynthesis is essential for survival and virulence of Mycobacterium tuberculosis. Mol Microbiol 78:980–988 http://dx.doi.org/10.1111/j.1365-2958.2010.07381.x.
53. Pavelka MS Jr, Chen B, Kelley CL, Collins FM, Jacobs WR Jr. 2003. Vaccine efficacy of a lysine auxotroph of Mycobacterium tuberculosis. Infect Immun 71:4190–4192 http://dx.doi.org/10.1128/IAI.71.7.4190-4192.2003.
54. Vilchèze C, Weinrick B, Wong KW, Chen B, Jacobs WR Jr. 2010. NAD+ auxotrophy is bacteriocidal for the tubercle bacilli. Mol Microbiol 76:365–377 http://dx.doi.org/10.1111/j.1365-2958.2010.07099.x.
55. Gordhan BG, Smith DA, Alderton H, McAdam RA, Bancroft GJ, Mizrahi V. 2002. Construction and phenotypic characterization of an auxotrophic mutant of Mycobacterium tuberculosis defective in l-arginine biosynthesis. Infect Immun 70:3080–3084 http://dx.doi.org/10.1128/IAI.70.6.3080-3084.2002.
56. Sambandamurthy VK, Wang X, Chen B, Russell RG, Derrick S, Collins FM, Morris SL, Jacobs WR Jr. 2002. A pantothenate auxotroph of Mycobacterium tuberculosis is highly attenuated and protects mice against tuberculosis. Nat Med 8:1171–1174 http://dx.doi.org/10.1038/nm765.
57. Berney M, Berney-Meyer L, Wong KW, Chen B, Chen M, Kim J, Wang J, Harris D, Parkhill J, Chan J, Wang F, Jacobs WR Jr. 2015. Essential roles of methionine and S-adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis. Proc Natl Acad Sci USA 112: 10008–10013 http://dx.doi.org/10.1073/pnas.1513033112.
58. Jain P, Hsu T, Arai M, Biermann K, Thaler DS, Nguyen A, González PA, Tufariello JM, Kriakov J, Chen B, Larsen MH, Jacobs WR Jr. 2014. Specialized transduction designed for precise high-throughput unmarked deletions in Mycobacterium tuberculosis. MBio 5:e01245-14 http://dx.doi.org/10.1128/mBio.01245-14.
59. Thompson RW, Pesce JT, Ramalingam T, Wilson MS, White S, Cheever AW, Ricklefs SM, Porcella SF, Li L, Ellies LG, Wynn TA. 2008. Cationic amino acid transporter-2 regulates immunity by modulating arginase activity. PLoS Pathog 4:e1000023 http://dx.doi.org/10.1371/journal.ppat.1000023.
60. Murray PJ. 2016. Amino acid auxotrophy as a system of immunological control nodes. Nat Immunol 17:132–139 http://dx.doi.org/10.1038/ni.3323.
61. Qualls JE, Murray PJ. 2016. Immunometabolism within the tuberculosis granuloma: amino acids, hypoxia, and cellular respiration. Semin Immunopathol 38:139–152 http://dx.doi.org/10.1007/s00281-015-0534-0.
62. El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, König T, Schleicher U, Koo MS, Kaplan G, Fitzgerald KA, Tuomanen EI, Orme IM, Kanneganti TD, Bogdan C, Wynn TA, Murray PJ. 2008. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9:1399–1406 http://dx.doi.org/10.1038/ni.1671.
63. Senaratne RH, De Silva AD, Williams SJ, Mougous JD, Reader JR, Zhang T, Chan S, Sidders B, Lee DH, Chan J, Bertozzi CR, Riley LW. 2006. 5′-Adenosinephosphosulphate reductase (CysH) protects Mycobacterium tuberculosis against free radicals during chronic infection phase in mice. Mol Microbiol 59:1744–1753 http://dx.doi.org/10.1111/j.1365-2958.2006.05075.x.
64. Wooff E, Michell SL, Gordon SV, Chambers MA, Bardarov S, Jacobs WR Jr, Hewinson RG, Wheeler PR. 2002. Functional genomics reveals the sole sulphate transporter of the Mycobacterium tuberculosis complex and its relevance to the acquisition of sulphur in vivo. Mol Microbiol 43:653–663 http://dx.doi.org/10.1046/j.1365-2958.2002.02771.x.
65. Hwang BJ, Yeom HJ, Kim Y, Lee HS. 2002. Corynebacterium glutamicum utilizes both transsulfuration and direct sulfhydrylation pathways for methionine biosynthesis. J Bacteriol 184:1277–1286 http://dx.doi.org/10.1128/JB.184.5.1277-1286.2002.
66. Parish T. 2003. Starvation survival response of Mycobacterium tuberculosis. J Bacteriol 185:6702–6706 http://dx.doi.org/10.1128/JB.185.22.6702-6706.2003.
67. Berney M, Weimar MR, Heikal A, Cook GM. 2012. Regulation of proline metabolism in mycobacteria and its role in carbon metabolism under hypoxia. Mol Microbiol 84:664–681 http://dx.doi.org/10.1111/j.1365-2958.2012.08053.x.
68. Lagautriere T, Bashiri G, Paterson NG, Berney M, Cook GM, Baker EN. 2014. Characterization of the proline-utilization pathway in Mycobacterium tuberculosis through structural and functional studies. Acta Crystallogr D Biol Crystallogr 70:968–980 http://dx.doi.org/10.1107/S1399004713034391.
69. Pavelka MS Jr, Jacobs WR Jr. 1999. Comparison of the construction of unmarked deletion mutations in Mycobacterium smegmatis, Mycobacterium bovis bacillus Calmette-Guérin, and Mycobacterium tuberculosis H37Rv by allelic exchange. J Bacteriol 181:4780–4789. [PubMed]
70. Sambandamurthy VK, Derrick SC, Jalapathy KV, Chen B, Russell RG, Morris SL, Jacobs WR Jr. 2005. Long-term protection against tuberculosis following vaccination with a severely attenuated double lysine and pantothenate auxotroph of Mycobacterium tuberculosis. Infect Immun 73:1196–1203 http://dx.doi.org/10.1128/IAI.73.2.1196-1203.2005.
71. Larsen MH, Biermann K, Chen B, Hsu T, Sambandamurthy VK, Lackner AA, Aye PP, Didier P, Huang D, Shao L, Wei H, Letvin NL, Frothingham R, Haynes BF, Chen ZW, Jacobs WR Jr. 2009. Efficacy and safety of live attenuated persistent and rapidly cleared Mycobacterium tuberculosis vaccine candidates in non-human primates. Vaccine 27:4709–4717 http://dx.doi.org/10.1016/j.vaccine.2009.05.050.
72. Covarrubias AS, Högbom M, Bergfors T, Carroll P, Mannerstedt K, Oscarson S, Parish T, Jones TA, Mowbray SL. 2008. Structural, biochemical, and in vivo investigations of the threonine synthase from Mycobacterium tuberculosis. J Mol Biol 381:622–633 http://dx.doi.org/10.1016/j.jmb.2008.05.086.
73. Sampson SL, Dascher CC, Sambandamurthy VK, Russell RG, Jacobs WR Jr, Bloom BR, Hondalus MK. 2004. Protection elicited by a double leucine and pantothenate auxotroph of Mycobacterium tuberculosis in guinea pigs. Infect Immun 72:3031–3037 http://dx.doi.org/10.1128/IAI.72.5.3031-3037.2004.
74. Awasthy D, Gaonkar S, Shandil RK, Yadav R, Bharath S, Marcel N, Subbulakshmi V, Sharma U. 2009. Inactivation of the ilvB1 gene in Mycobacterium tuberculosis leads to branched-chain amino acid auxotrophy and attenuation of virulence in mice. Microbiology 155:2978–2987 http://dx.doi.org/10.1099/mic.0.029884-0.
75. Wherry JC, Schreiber RD, Unanue ER. 1991. Regulation of gamma interferon production by natural killer cells in scid mice: roles of tumor necrosis factor and bacterial stimuli. Infect Immun 59:1709–1715. [PubMed]
76. Hayward AR, Chmura K, Cosyns M. 2000. Interferon-gamma is required for innate immunity to Cryptosporidium parvum in mice. J Infect Dis 182:1001–1004 http://dx.doi.org/10.1086/315802.
77. Bell LV, Else KJ. 2011. Regulation of colonic epithelial cell turnover by IDO contributes to the innate susceptibility of SCID mice to Trichuris muris infection. Parasite Immunol 33:244–249 http://dx.doi.org/10.1111/j.1365-3024.2010.01272.x.
78. Harth G, Maslesa-Galić S, Tullius MV, Horwitz MA. 2005. All four Mycobacterium tuberculosis glnA genes encode glutamine synthetase activities but only GlnA1 is abundantly expressed and essential for bacterial homeostasis. Mol Microbiol 58:1157–1172 http://dx.doi.org/10.1111/j.1365-2958.2005.04899.x.
79. Tullius MV, Harth G, Horwitz MA. 2003. Glutamine synthetase GlnA1 is essential for growth of Mycobacterium tuberculosis in human THP-1 macrophages and guinea pigs. Infect Immun 71:3927–3936 http://dx.doi.org/10.1128/IAI.71.7.3927-3936.2003.
80. Harth G, Horwitz MA. 2003. Inhibition of Mycobacterium tuberculosis glutamine synthetase as a novel antibiotic strategy against tuberculosis: demonstration of efficacy in vivo. Infect Immun 71:456–464 http://dx.doi.org/10.1128/IAI.71.1.456-464.2003.
81. Tullius MV, Harth G, Horwitz MA. 2001. High extracellular levels of Mycobacterium tuberculosis glutamine synthetase and superoxide dismutase in actively growing cultures are due to high expression and extracellular stability rather than to a protein-specific export mechanism. Infect Immun 69:6348–6363 http://dx.doi.org/10.1128/IAI.69.10.6348-6363.2001.
82. Mowbray SL, Kathiravan MK, Pandey AA, Odell LR. 2014. Inhibition of glutamine synthetase: a potential drug target in Mycobacterium tuberculosis. Molecules 19:13161–13176 http://dx.doi.org/10.3390/molecules190913161.
83. Gouzy A, Poquet Y, Neyrolles O. 2014. Nitrogen metabolism in Mycobacterium tuberculosis physiology and virulence. Nat Rev Microbiol 12:729–737 http://dx.doi.org/10.1038/nrmicro3349.
84. Doucette CD, Schwab DJ, Wingreen NS, Rabinowitz JD. 2011. α-Ketoglutarate coordinates carbon and nitrogen utilization via enzyme I inhibition. Nat Chem Biol 7:894–901 http://dx.doi.org/10.1038/nchembio.685.
85. Lyon RH, Hall WH, Costas-Martinez C. 1970. Utilization of amino acids during growth of Mycobacterium tuberculosis in rotary cultures. Infect Immun 1:513–520. [PubMed]
86. Song H, Niederweis M. 2012. Uptake of sulfate but not phosphate by Mycobacterium tuberculosis is slower than that for Mycobacterium smegmatis. J Bacteriol 194:956–964 http://dx.doi.org/10.1128/JB.06132-11.
87. Cowley S, Ko M, Pick N, Chow R, Downing KJ, Gordhan BG, Betts JC, Mizrahi V, Smith DA, Stokes RW, Av-Gay Y. 2004. The Mycobacterium tuberculosis protein serine/threonine kinase PknG is linked to cellular glutamate/glutamine levels and is important for growth in vivo. Mol Microbiol 52:1691–1702 http://dx.doi.org/10.1111/j.1365-2958.2004.04085.x.
88. Ventura M, Rieck B, Boldrin F, Degiacomi G, Bellinzoni M, Barilone N, Alzaidi F, Alzari PM, Manganelli R, O’Hare HM. 2013. GarA is an essential regulator of metabolism in Mycobacterium tuberculosis. Mol Microbiol 90:356–366. [PubMed]
89. Gallant JL, Viljoen AJ, van Helden PD, Wiid IJ. 2016. Glutamate dehydrogenase is required by Mycobacterium bovis BCG for resistance to cellular stress. PLoS One 11:e0147706 http://dx.doi.org/10.1371/journal.pone.0147706.
90. Viljoen AJ, Kirsten CJ, Baker B, van Helden PD, Wiid IJ. 2013. The role of glutamine oxoglutarate aminotransferase and glutamate dehydrogenase in nitrogen metabolism in Mycobacterium bovis BCG. PLoS One 8:e84452 http://dx.doi.org/10.1371/journal.pone.0084452.
91. Boshoff HI, Xu X, Tahlan K, Dowd CS, Pethe K, Camacho LR, Park TH, Yun CS, Schnappinger D, Ehrt S, Williams KJ, Barry CE III. 2008. Biosynthesis and recycling of nicotinamide cofactors in Mycobacterium tuberculosis. An essential role for NAD in nonreplicating bacilli. J Biol Chem 283:19329–19341 http://dx.doi.org/10.1074/jbc.M800694200.
92. Kim JH, O’Brien KM, Sharma R, Boshoff HI, Rehren G, Chakraborty S, Wallach JB, Monteleone M, Wilson DJ, Aldrich CC, Barry CE III, Rhee KY, Ehrt S, Schnappinger D. 2013. A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence. Proc Natl Acad Sci USA 110:19095–19100 http://dx.doi.org/10.1073/pnas.1315860110.
93. Rodionova IA, Schuster BM, Guinn KM, Sorci L, Scott DA, Li X, Kheterpal I, Shoen C, Cynamon M, Locher C, Rubin EJ, Osterman AL. 2014. Metabolic and bactericidal effects of targeted suppression of NadD and NadE enzymes in mycobacteria. MBio 5:e00747-13 http://dx.doi.org/10.1128/mBio.00747-13.
94. Reddy BK, Landge S, Ravishankar S, Patil V, Shinde V, Tantry S, Kale M, Raichurkar A, Menasinakai S, Mudugal NV, Ambady A, Ghosh A, Tunduguru R, Kaur P, Singh R, Kumar N, Bharath S, Sundaram A, Bhat J, Sambandamurthy VK, Björkelid C, Jones TA, Das K, Bandodkar B, Malolanarasimhan K, Mukherjee K, Ramachandran V. 2014. Assessment of Mycobacterium tuberculosis pantothenate kinase vulnerability through target knockdown and mechanistically diverse inhibitors. Antimicrob Agents Chemother 58:3312–3326 http://dx.doi.org/10.1128/AAC.00140-14.
95. Sambandamurthy VK, Jacobs WR Jr. 2005. Live attenuated mutants of Mycobacterium tuberculosis as candidate vaccines against tuberculosis. Microbes Infect 7:955–961 http://dx.doi.org/10.1016/j.micinf.2005.04.001.
96. Gengenbacher M, Vogelzang A, Schuerer S, Lazar D, Kaiser P, Kaufmann SH. 2014. Dietary pyridoxine controls efficacy of vitamin B6-auxotrophic tuberculosis vaccine bacillus Calmette-Guérin ΔureC:hly Δpdx1 in mice. MBio 5:e01262-14 http://dx.doi.org/10.1128/mBio.01262-14.
97. Salaemae W, Booker GW, Polyak SW. 2016. The role of biotin in bacterial physiology and virulence: a novel antibiotic target for Mycobacterium tuberculosis. Microbiol Spectr 4:VMBF-0008-2015. doi:10.1128/microbiolspec.VMBF-0008-2015.
98. Park SW, Casalena DE, Wilson DJ, Dai R, Nag PP, Liu F, Boyce JP, Bittker JA, Schreiber SL, Finzel BC, Schnappinger D, Aldrich CC. 2015. Target-based identification of whole-cell active inhibitors of biotin biosynthesis in Mycobacterium tuberculosis. Chem Biol 22:76–86 http://dx.doi.org/10.1016/j.chembiol.2014.11.012.
99. Kana BD, Karakousis PC, Parish T, Dick T. 2014. Future target-based drug discovery for tuberculosis? Tuberculosis (Edinb) 94:551–556 http://dx.doi.org/10.1016/j.tube.2014.10.003.
100. Gengenbacher M, Dick T. 2015. Antibacterial drug discovery: doing it right. Chem Biol 22:5–6 http://dx.doi.org/10.1016/j.chembiol.2014.12.005.
101. Nixon MR, Saionz KW, Koo MS, Szymonifka MJ, Jung H, Roberts JP, Nandakumar M, Kumar A, Liao R, Rustad T, Sacchettini JC, Rhee KY, Freundlich JS, Sherman DR. 2014. Folate pathway disruption leads to critical disruption of methionine derivatives in Mycobacterium tuberculosis. Chem Biol 21:819–830 http://dx.doi.org/10.1016/j.chembiol.2014.04.009.
102. Minato Y, Thiede JM, Kordus SL, McKlveen EJ, Turman BJ, Baughn AD. 2015. Mycobacterium tuberculosis folate metabolism and the mechanistic basis for para-aminosalicylic acid susceptibility and resistance. Antimicrob Agents Chemother 59:5097–5106 http://dx.doi.org/10.1128/AAC.00647-15.
103. Chakraborty S, Gruber T, Barry CE III, Boshoff HI, Rhee KY. 2013. Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis. Science 339:88–91 http://dx.doi.org/10.1126/science.1228980.
104. Lehmann J. 1946. Para-aminosalicylic acid in the treatment of tuberculosis. Lancet 247:15–16 http://dx.doi.org/10.1016/S0140-6736(46)91185-3.
105. Kumar A, Zhang M, Zhu L, Liao RP, Mutai C, Hafsat S, Sherman DR, Wang MW. 2012. High-throughput screening and sensitized bacteria identify an M. tuberculosis dihydrofolate reductase inhibitor with whole cell activity. PLoS One 7:e39961 http://dx.doi.org/10.1371/journal.pone.0039961.
106. Kumar A, Guardia A, Colmenarejo G, Pérez E, Gonzalez RR, Torres P, Calvo D, Gómez RM, Ortega F, Jiménez E, Gabarro RC, Rullás J, Ballell L, Sherman DR. 2015. A focused screen identifies antifolates with activity on Mycobacterium tuberculosis. ACS Infect Dis 1:604–614 http://dx.doi.org/10.1021/acsinfecdis.5b00063.
107. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE III, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544 http://dx.doi.org/10.1038/31159.
108. Gopinath K, Moosa A, Mizrahi V, Warner DF. 2013. Vitamin B(12) metabolism in Mycobacterium tuberculosis. Future Microbiol 8:1405–1418 http://dx.doi.org/10.2217/fmb.13.113.
109. Young DB, Comas I, de Carvalho LP. 2015. Phylogenetic analysis of vitamin B12-related metabolism in Mycobacterium tuberculosis. Front Mol Biosci 2:6 http://dx.doi.org/10.3389/fmolb.2015.00006.
110. Griffin JE, Pandey AK, Gilmore SA, Mizrahi V, McKinney JD, Bertozzi CR, Sassetti CM. 2012. Cholesterol catabolism by Mycobacterium tuberculosis requires transcriptional and metabolic adaptations. Chem Biol 19:218–227 http://dx.doi.org/10.1016/j.chembiol.2011.12.016.
111. Savvi S, Warner DF, Kana BD, McKinney JD, Mizrahi V, Dawes SS. 2008. Functional characterization of a vitamin B12-dependent methylmalonyl pathway in Mycobacterium tuberculosis: implications for propionate metabolism during growth on fatty acids. J Bacteriol 190:3886–3895 http://dx.doi.org/10.1128/JB.01767-07.
112. Lee W, VanderVen BC, Fahey RJ, Russell DG. 2013. Intracellular Mycobacterium tuberculosis exploits host-derived fatty acids to limit metabolic stress. J Biol Chem 288:6788–6800 http://dx.doi.org/10.1074/jbc.M112.445056.
113. Warner DF, Savvi S, Mizrahi V, Dawes SS. 2007. A riboswitch regulates expression of the coenzyme B12-independent methionine synthase in Mycobacterium tuberculosis: implications for differential methionine synthase function in strains H37Rv and CDC1551. J Bacteriol 189:3655–3659 http://dx.doi.org/10.1128/JB.00040-07.
114. Gopinath K, Venclovas C, Ioerger TR, Sacchettini JC, McKinney JD, Mizrahi V, Warner DF. 2013. A vitamin B 12 transporter in Mycobacterium tuberculosis. Open Biol 3:120175 http://dx.doi.org/10.1098/rsob.120175.
115. Jackson M, Phalen SW, Lagranderie M, Ensergueix D, Chavarot P, Marchal G, McMurray DN, Gicquel B, Guilhot C. 1999. Persistence and protective efficacy of a Mycobacterium tuberculosis auxotroph vaccine. Infect Immun 67:2867–2873. [PubMed]
116. Senaratne RH, Mougous JD, Reader JR, Williams SJ, Zhang T, Bertozzi CR, Riley LW. 2007. Vaccine efficacy of an attenuated but persistent Mycobacterium tuberculosis cysH mutant. J Med Microbiol 56:454–458 http://dx.doi.org/10.1099/jmm.0.46983-0.
117. Niederweis M. 2008. Nutrient acquisition by mycobacteria. Microbiology 154:679–692 http://dx.doi.org/10.1099/mic.0.2007/012872-0.
118. Yu XJ, Walker DH, Liu Y, Zhang L. 2009. Amino acid biosynthesis deficiency in bacteria associated with human and animal hosts. Infect Genet Evol 9:514–517 http://dx.doi.org/10.1016/j.meegid.2009.02.002.
119. Gómez-Valero L, Rocha EP, Latorre A, Silva FJ. 2007. Reconstructing the ancestor of Mycobacterium leprae: the dynamics of gene loss and genome reduction. Genome Res 17:1178–1185 http://dx.doi.org/10.1101/gr.6360207.
120. Rohmer L, Hocquet D, Miller SI. 2011. Are pathogenic bacteria just looking for food? Metabolism and microbial pathogenesis. Trends Microbiol 19:341–348 http://dx.doi.org/10.1016/j.tim.2011.04.003.
121. Houben EN, Korotkov KV, Bitter W. 2014. Take five: type VII secretion systems of mycobacteria. Biochim Biophys Acta 1843:1707–1716 http://dx.doi.org/10.1016/j.bbamcr.2013.11.003.
122. Tufariello JM, Chapman JR, Kerantzas CA, Wong KW, Vilchèze C, Jones CM, Cole LE, Tinaztepe E, Thompson V, Fenyö D, Niederweis M, Ueberheide B, Philips JA, Jacobs WR Jr. 2016. Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence. Proc Natl Acad Sci USA 113:E348–E357 http://dx.doi.org/10.1073/pnas.1523321113.
123. Marquis H, Bouwer HG, Hinrichs DJ, Portnoy DA. 1993. Intracytoplasmic growth and virulence of Listeria monocytogenes auxotrophic mutants. Infect Immun 61:3756–3760. [PubMed]
124. Premaratne RJ, Lin WJ, Johnson EA. 1991. Development of an improved chemically defined minimal medium for Listeria monocytogenes. Appl Environ Microbiol 57:3046–3048. [PubMed]
125. Portnoy DA, Jacks PS, Hinrichs DJ. 1988. Role of hemolysin for the intracellular growth of Listeria monocytogenes. J Exp Med 167:1459–1471 http://dx.doi.org/10.1084/jem.167.4.1459.
126. Abu Kwaik Y, Bumann D. 2015. Host delivery of favorite meals for intracellular pathogens. PLoS Pathog 11:e1004866 http://dx.doi.org/10.1371/journal.ppat.1004866.
127. Ihssen J, Egli T. 2005. Global physiological analysis of carbon- and energy-limited growing Escherichia coli confirms a high degree of catabolic flexibility and preparedness for mixed substrate utilization. Environ Microbiol 7:1568–1581 http://dx.doi.org/10.1111/j.1462-2920.2005.00846.x.
128. Cohen SS, Barner HD. 1954. Studies on unbalanced growth in Escherichia coli. Proc Natl Acad Sci USA 40:885–893 http://dx.doi.org/10.1073/pnas.40.10.885.
129. Hall JD, Craven RR, Fuller JR, Pickles RJ, Kawula TH. 2007. Francisella tularensis replicates within alveolar type II epithelial cells in vitro and in vivo following inhalation. Infect Immun 75:1034–1039. [PubMed]
130. Horwitz MA. 1983. The Legionnaires’ disease bacterium ( Legionella pneumophila) inhibits phagosome-lysosome fusion in human monocytes. J Exp Med 158:2108–2126. [PubMed]
131. Marquis H, Bouwer HG, Hinrichs DJ, Portnoy DA. 1993. Intracytoplasmic growth and virulence of Listeria monocytogenes auxotrophic mutants. Infect Immun 61:3756–3760. [PubMed]

Article metrics loading...



Coevolution of pathogens and host has led to many metabolic strategies employed by intracellular pathogens to deal with the immune response and the scarcity of food during infection. Simply put, bacterial pathogens are just looking for food. As a consequence, the host has developed strategies to limit nutrients for the bacterium by containment of the intruder in a pathogen-containing vacuole and/or by actively depleting nutrients from the intracellular space, a process called nutritional immunity. Since metabolism is a prerequisite for virulence, such pathways could potentially be good targets for antimicrobial therapies. In this chapter, we review the current knowledge about the diet of , with a focus on amino acid and cofactors, discuss evidence for the bacilli’s nutritionally independent lifestyle in the host, and evaluate strategies for new chemotherapeutic interventions.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Supplemental Material

No supplementary material available for this content.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error