1887

Abstract

(Mtb) is an obligate human pathogen killing millions of people annually. Treatment for tuberculosis is lengthy and complicated, involving multiple drugs and often resulting in serious side effects and non-compliance. Mtb has developed numerous complex mechanisms enabling it to not only survive but replicate inside professional phagocytes. These mechanisms include, among others, overcoming the phagosome maturation process, inhibiting the acidification of the phagosome and inhibiting apoptosis. Within the past decade, technologies have been developed that enable a more accurate understanding of Mtb physiology within its intracellular niche, paving the way for more clinically relevant drug-development programmes. Here we review the molecular biology of Mtb pathogenesis offering a unique perspective on the use and development of therapies that target Mtb during its intracellular life stage.

Funding
This study was supported by the:
  • CIHR (Award PJT-148646 and PJT-152931)
    • Principle Award Recipient: YossefAv-Gay
Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.001041
2021-04-07
2021-04-14
Loading full text...

Full text loading...

/deliver/fulltext/micro/167/4/mic001041.html?itemId=/content/journal/micro/10.1099/mic.0.001041&mimeType=html&fmt=ahah

References

  1. World Health Organization Global Tuberculosis Report France: 2018
    [Google Scholar]
  2. Soeroto AY, Lestari BW, Santoso P, Chaidir L, Andriyoko B et al. Evaluation of Xpert MTB-RIF guided diagnosis and treatment of rifampicin-resistant tuberculosis in Indonesia: a retrospective cohort study. PLoS One 2019; 14:e0213017
    [Google Scholar]
  3. Hmama Z, Peña-Díaz S, Joseph S, Av-Gay Y. Immunoevasion and immunosuppression of the macrophage by Mycobacterium tuberculosis . Immunol Rev 2015; 264:220–232
    [Google Scholar]
  4. Kroesen VM, Groschel MI, Martinson N, Zumla A, Maeurer M et al. Non-Steroidal anti-inflammatory drugs as Host-Directed therapy for tuberculosis: a systematic review. Front Immunol 2017; 8:772
    [Google Scholar]
  5. Padmapriyadarsini C, Bhavani PK, Natrajan M, Ponnuraja C, Kumar H et al. Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial. BMJ Open 2019; 9:e024363
    [Google Scholar]
  6. Simões MF, Ottoni CA, Antunes A. Mycogenic metal nanoparticles for the treatment of mycobacterioses. Antibiot 2020; 9:
    [Google Scholar]
  7. Jafari A, Nagheli A, Foumani AA, Soltani B, Goswami R. The role of metallic nanoparticles in inhibition of Mycobacterium tuberculosis and enhances phagosome maturation into the infected macrophage. Oman Med J 2020; 35:e194
    [Google Scholar]
  8. Tăbăran A-F, Matea CT, Mocan T, Tăbăran A, Mihaiu M et al. Silver nanoparticles for the therapy of tuberculosis. Int J Nanomedicine 2020; 15:2231–2258
    [Google Scholar]
  9. Jensen MS, Bainton DF. Temporal changes in pH within the phagocytic vacuole of the polymorphonuclear neutrophilic leukocyte. J Cell Biol 1973; 56:379–388
    [Google Scholar]
  10. Poirier V, Av-Gay Y. Intracellular growth of bacterial pathogens: the role of secreted effector proteins in the control of phagocytosed microorganisms. Microbiol Spectr. 2015; 3:
    [Google Scholar]
  11. Denzin LK, Cresswell P. Hla-Dm induces clip dissociation from MHC class II alpha beta dimers and facilitates peptide loading. Cell 1995; 82:155–165
    [Google Scholar]
  12. Vieira O V, Botelho RJ, Grinstein S. Phagosome maturation: aging gracefully. Biochem J . 2002 Sep 15; 366:689–704
    [Google Scholar]
  13. Fratti RA, Chua J, Vergne I, Deretic V. Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Proc Natl Acad Sci 2003; 100:5437–5442
    [Google Scholar]
  14. Deretic V, Singh S, Master S, Harris J, Roberts E et al. Mycobacterium tuberculosis inhibition of phagolysosome biogenesis and autophagy as a host defence mechanism. Cell Microbiol 2006; 8:719–727
    [Google Scholar]
  15. Fratti RA, Backer JM, Gruenberg J, Corvera S, Deretic V. Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J Cell Biol 2001; 154:631–644
    [Google Scholar]
  16. Hu C, Ahmed M, Melia TJ, Sollner TH, Mayer T et al. Fusion of cells by flipped SNAREs. Science 2003; 300:1745–1749
    [Google Scholar]
  17. Rink J, Ghigo E, Kalaidzidis Y, Zerial M. Rab conversion as a mechanism of progression from early to late endosomes. Cell 2005; 122:735–749
    [Google Scholar]
  18. Balderhaar HJk, Ungermann C. CORVET and HOPS tethering complexes - coordinators of endosome and lysosome fusion. J Cell Sci 2013; 126:1307–1316 [CrossRef]
    [Google Scholar]
  19. Jordens I, Fernandez-Borja M, Marsman M, Dusseljee S, Janssen L et al. The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors. Curr Biol 2001; 11:1680–1685
    [Google Scholar]
  20. Harrison RE, Bucci C, Vieira OV, Schroer TA, Grinstein S. Phagosomes fuse with late endosomes and/or lysosomes by extension of membrane protrusions along microtubules: role of Rab7 and RILP. Mol Cell Biol 2003; 23:6494–6506 [CrossRef][PubMed]
    [Google Scholar]
  21. Zulauf KE, Sullivan JT, Braunstein M. The SecA2 pathway of Mycobacterium tuberculosis exports effectors that work in concert to arrest phagosome and autophagosome maturation. PLoS Pathog 2018; 14:1–29
    [Google Scholar]
  22. Vergne I, Chua J, Lee H-H, Lucas M, Belisle J et al. Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis . Proc Natl Acad Sci U S A 2005; 102:4033–4038
    [Google Scholar]
  23. Walburger A, Koul A, Ferrari G, Nguyen L, Prescianotto-Baschong C et al. Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 2004; 304:1800–1804
    [Google Scholar]
  24. Wong D, Bach H, Sun J, Hmama Z, Av-Gay Y. Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification. Proc Natl Acad Sci 2011; 108:19371–19376
    [Google Scholar]
  25. Christoforidis S, Miaczynska M, Ashman K, Wilm M, Zhao L et al. Phosphatidylinositol-3-Oh kinases are Rab5 effectors. Nat Cell Biol 1999; 1:249–252
    [Google Scholar]
  26. Chua J, Deretic V. Mycobacterium tuberculosis reprograms waves of phosphatidylinositol 3-phosphate on phagosomal organelles. J Biol Chem 2004; 279:36982–36992
    [Google Scholar]
  27. Rajaram MVS, Arnett E, Azad AK, Guirado E, Ni B et al. M. tuberculosis-initiated human mannose receptor signaling regulates macrophage recognition and vesicle trafficking by FcRgamma-Chain, Grb2, and SHP-1. Cell Rep 2017; 21:126–140
    [Google Scholar]
  28. Fernandez-Soto P, Bruce AJE, Fielding AJ, Cavet JS, Tabernero L. Mechanism of catalysis and inhibition of Mycobacterium tuberculosis SapM, implications for the development of novel antivirulence drugs. Sci Rep 2019; 9:10315
    [Google Scholar]
  29. Fernandez-Soto P, Cavet JS, Tabernero L. Expression and purification of soluble recombinant SapM from Mycobacterium tuberculosis. Protein Expr Purif 2020; 174:105663
    [Google Scholar]
  30. Park H-J, Lee SJ, Kim S-H, Han J, Bae J et al. Il-10 inhibits the starvation induced autophagy in macrophages via class I phosphatidylinositol 3-kinase (PI3K) pathway. Mol Immunol 2011; 48:720–727
    [Google Scholar]
  31. Harris J, De Haro SA, Master SS, Keane J, Roberts EA et al. T Helper 2 Cytokines Inhibit Autophagic Control of Intracellular Mycobacterium tuberculosis . Immunity 2007; 27:505–517
    [Google Scholar]
  32. Roberts EA, Chua J, Kyei GB, Deretic V. Higher order Rab programming in phagolysosome biogenesis. J Cell Biol. 2006/09/18 2006; 174:923–929
    [Google Scholar]
  33. Chandra P, Ghanwat S, Matta SK, Yadav SS, Mehta M et al. Mycobacterium tuberculosis Inhibits RAB7 Recruitment to Selectively Modulate Autophagy Flux in Macrophages. Sci Rep 2015; 5:1–10
    [Google Scholar]
  34. van der Woude AD, Stoop EJM, Stiess M, Wang S, Ummels R et al. Analysis of SecA2-dependent substrates in Mycobacterium marinum identifies protein kinase G (PknG) as a virulence effector. Cell Microbiol 2014; 16:280–295
    [Google Scholar]
  35. Hinchey J, Jeon BY, Alley H, Chen B, Goldberg M et al. Lysine auxotrophy combined with deletion of the SecA2 gene results in a safe and highly immunogenic candidate live attenuated vaccine for tuberculosis. PLoS One. 2011; 6:e15857
    [Google Scholar]
  36. Saikolappan S, Estrella J, Sasindran SJ, Khan A, Armitige LY et al. The fbpA/sapM double knock out strain of Mycobacterium tuberculosis is highly attenuated and immunogenic in macrophages. PLoS One 2012; 7:e36198
    [Google Scholar]
  37. Vilchèze C, Hartman T, Weinrick B, Jacobs WRJ. Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction. Nat Commun 1881; 2013:4
    [Google Scholar]
  38. Vilchèze C, Kim J, Jacobs WR. Vitamin C potentiates the killing of Mycobacterium tuberculosis by the first-line tuberculosis drugs isoniazid and rifampin in mice. Antimicrob Agents Chemother 2018; 62:
    [Google Scholar]
  39. Maniak M, Rauchenberger R, Albrecht R, Murphy J, Gerisch G. Coronin involved in phagocytosis: dynamics of particle-induced relocalization visualized by a green fluorescent protein tag. Cell 1995; 83:915–924
    [Google Scholar]
  40. Ferrari G, Langen H, Naito M, Pieters J. A coat protein on phagosomes involved in the intracellular survival of mycobacteria. Cell 1999; 97:435–447
    [Google Scholar]
  41. Nguyen L, Pieters J. The Trojan horse: survival tactics of pathogenic mycobacteria in macrophages. Trends Cell Biol 2005; 15:269–276
    [Google Scholar]
  42. Hestvik ALK, Av-Gay Y, Hmama Z. Mycobacterial manipulation of the host cell. FEMS Microbiol Rev 2005; 29:1041–1050
    [Google Scholar]
  43. Vergne I, Chua J, Deretic V. Mycobacterium tuberculosis phagosome maturation arrest: selective targeting of PI3P-dependent membrane trafficking. Traffic 2003; 4:600–606
    [Google Scholar]
  44. Jayachandran R, Sundaramurthy V, Combaluzier B, Mueller P, Korf H et al. Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin. Cell 2007; 130:37–50
    [Google Scholar]
  45. Trimble WS, Grinstein S. Tb or not TB: calcium regulation in mycobacterial survival. Cell 2007; 130:12–14
    [Google Scholar]
  46. Poirier V, Bach H, Av-Gay Y. Mycobacterium tuberculosis Promotes Anti-apoptotic Activity of the Macrophage by PtpA Protein-dependent Dephosphorylation of Host GSK3α. J Biol Chem 2014; 289:29376–29385
    [Google Scholar]
  47. Bach H, Papavinasasundaram KG, Wong D, Hmama Z, Av-Gay Y. Mycobacterium tuberculosis Virulence Is Mediated by PtpA Dephosphorylation of Human Vacuolar Protein Sorting 33B. Cell Host Microbe 2008; 3:316–322
    [Google Scholar]
  48. Chao J, Wong D, Zheng X, Poirier V, Bach H et al. Protein kinase and phosphatase signaling in Mycobacterium tuberculosis physiology and pathogenesis. Biochim Biophys Acta - Proteins Proteomics 1804; 2010:620–627
    [Google Scholar]
  49. Bach H, Wong D, Av-Gay Y. Mycobacterium tuberculosis PtkA is a novel protein tyrosine kinase whose substrate is PtpA. Biochem J 2009; 420:155–162
    [Google Scholar]
  50. Zhou P, Wong D, Li W, Xie J, Av-Gay Y. Phosphorylation of Mycobacterium tuberculosis protein tyrosine kinase A PtkA by Ser/Thr protein kinases. Biochem Biophys Res Commun 2015
    [Google Scholar]
  51. Wong D, Li W, Chao JD, Zhou P, Narula G et al. Protein tyrosine kinase, PtkA, is required for Mycobacterium tuberculosis growth in macrophages. Sci Rep 2018; 8:155
    [Google Scholar]
  52. Bach H, Sun J, Hmama Z, Av-Gay Y. Mycobacterium avium subsp. paratuberculosis PtpA is an endogenous tyrosine phosphatase secreted during infection. Infect Immun 2006; 74:6540–6546
    [Google Scholar]
  53. Poirier V. Molecular Analysis of Mycobacterium tuberculosis Infection of Human Macrophages: The Role of Protein Tyrosine Phosphatase A The University Of British Columbia; 2015
    [Google Scholar]
  54. Hestvik ALK, Hmama Z, Av-Gay Y. Kinome analysis of host response to mycobacterial infection: a novel technique in proteomics. Infect Immun 2003; 71:5514–5522
    [Google Scholar]
  55. Wang J, Ge P, Qiang L, Tian F, Zhao D et al. The mycobacterial phosphatase PtpA regulates the expression of host genes and promotes cell proliferation. Nat Commun 2017; 8:
    [Google Scholar]
  56. Manger M, Scheck M, Prinz H, von Kries JP, Langer T et al. Discovery of Mycobacterium tuberculosis Protein Tyrosine Phosphatase A (MptpA) inhibitors based on natural products and a fragment-based approach. ChemBioChem 2005; 6:1749–1753
    [Google Scholar]
  57. Stehle T, Sreeramulu S, Lohr F, Richter C, Saxena K et al. The apo-structure of the low molecular weight protein-tyrosine phosphatase A (MptpA) from Mycobacterium tuberculosis allows for better target-specific drug development. J Biol Chem 2012; 287:34569–34582
    [Google Scholar]
  58. Rawls KA, Lang PT, Takeuchi J, Imamura S, Baguley TD et al. Fragment-based discovery of selective inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. Bioorg Med Chem Lett 2009; 19:6851–6854
    [Google Scholar]
  59. Mascarello A, Mori M, Chiaradia-Delatorre LD, Menegatti ACO, Delle Monache F et al. Discovery of Mycobacterium tuberculosis protein tyrosine phosphatase B (PtpB) inhibitors from natural products. PLoS One 2013; 8:e77081 [CrossRef][PubMed]
    [Google Scholar]
  60. Dutta NK, He R, Pinn ML, He Y, Burrows F et al. Mycobacterial protein tyrosine phosphatases A and B inhibitors augment the bactericidal activity of the standard anti-tuberculosis regimen. ACS Infect Dis 2016; 2:231–239
    [Google Scholar]
  61. Mascarello A, Chiaradia LD, Vernal J, Villarino A, Guido RVC et al. Inhibition of Mycobacterium tuberculosis tyrosine phosphatase PtpA by synthetic chalcones: kinetics, molecular modeling, toxicity and effect on growth. Bioorg Med Chem 2010; 18:3783–3789
    [Google Scholar]
  62. Margenat M, Labandera A-M, Gil M, Carrion F, Purificação M et al. New potential eukaryotic substrates of the mycobacterial protein tyrosine phosphatase PtpA: hints of a bacterial modulation of macrophage bioenergetics state. Sci Rep 2015; 5:8819
    [Google Scholar]
  63. Savalas LRT, Furqon BRN, Asnawati D, ’Ardhuha J, Sedijani P et al. Cis-2 and trans-2-eisocenoic fatty acids are novel inhibitors for Mycobacterium tuberculosis Protein tyrosine phosphatase A. Acta Biochim Pol 2020; 67:219–223
    [Google Scholar]
  64. Mori M, Sammartino JC, Costantino L, Gelain A, Meneghetti F et al. An overview on the potential antimycobacterial agents targeting serine/threonine protein kinases from Mycobacterium tuberculosis . Curr Top Med Chem 2019; 19:646–661
    [Google Scholar]
  65. Nagpal P, Jamal S, Singh H, Ali W, Tanweer S et al. Long-range replica exchange molecular dynamics guided drug repurposing against tyrosine kinase PtkA of Mycobacterium tuberculosis . Sci Rep 2020; 10:4413
    [Google Scholar]
  66. Lu J, Holmgren A. The thioredoxin antioxidant system. Free Radic Biol Med 2014; 66:75–87
    [Google Scholar]
  67. Lin K, O’Brien KM, Trujillo C, Wang R, Wallach JB et al. Mycobacterium tuberculosis thioredoxin reductase is essential for thiol redox homeostasis but plays a minor role in antioxidant defense. PLOS Pathog 2016; 12:e1005675
    [Google Scholar]
  68. Av-Gay Y, Everett M. The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis . Trends Microbiol 2000; 8:238–244
    [Google Scholar]
  69. Scherr N, Honnappa S, Kunz G, Mueller P, Jayachandran R et al. Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis . Proc Natl Acad Sci U S A 2007; 104:12151–12156
    [Google Scholar]
  70. Tiwari D, Singh RK, Goswami K, Verma SK, Prakash B et al. Key residues in Mycobacterium tuberculosis protein kinase G play a role in regulating kinase activity and survival in the host. J Biol Chem 2009; 284:27467–27479
    [Google Scholar]
  71. Cowley S, Ko M, Pick N, Chow R, Downing KJ et al. The Mycobacterium tuberculosis protein serine/threonine kinase PknG is linked to cellular glutamate/glutamine levels and is important for growth in vivo . Mol Microbiol 2004; 52:1691–1702
    [Google Scholar]
  72. O’Hare HM, Duran R, Cervenansky C, Bellinzoni M, Wehenkel AM et al. Regulation of glutamate metabolism by protein kinases in mycobacteria. Mol Microbiol 2008; 70:1408–1423
    [Google Scholar]
  73. Bhattacharyya N, Nkumama IN, Newland-Smith Z, Lin L-Y, Yin W et al. An Aspartate-Specific solute-binding protein regulates protein kinase G activity to control glutamate metabolism in mycobacteria. MBio 2018; 9:
    [Google Scholar]
  74. Khan MZ, Bhaskar A, Upadhyay S, Kumari P, Rajmani RS et al. Protein kinase G confers survival advantage to Mycobacterium tuberculosis during latency-like conditions. J Biol Chem 2017; 292:16093–16108
    [Google Scholar]
  75. Paroha R, Chourasia R, Mondal R, Chaurasiya SK. PknG supports mycobacterial adaptation in acidic environment. Mol Cell Biochem 2018; 443:69–80
    [Google Scholar]
  76. Gil M, Lima A, Rivera B, Rossello J, Urdaniz E et al. New substrates and interactors of the mycobacterial serine/threonine protein kinase PknG identified by a tailored interactomic approach. J Proteomics 2019; 192:321–333
    [Google Scholar]
  77. Baros SS, Blackburn JM, Soares NC. Phosphoproteomic approaches to discover novel substrates of mycobacterial Ser/Thr protein kinases. Mol Cell Proteomics 2020; 19:233–244
    [Google Scholar]
  78. Chakraborti PK, Matange N, Nandicoori VK, Singh Y, Tyagi JS et al. Signalling mechanisms in mycobacteria. Tuberculosis 2011; 91:432–440
    [Google Scholar]
  79. Walburger A, Koul A, Ferrari G, Nguyen L, Prescianotto-Baschong C et al. Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 2004; 304:1800–1804
    [Google Scholar]
  80. F-L W, Liu Y, Zhang H-N, Jiang H-W, Cheng L et al. Global profiling of PknG interactions using a human proteome microarray reveals novel connections with CypA. Proteomics 2018; 18:e1800265
    [Google Scholar]
  81. Pradhan G, Shrivastva R, Mukhopadhyay S. Mycobacterial PknG targets the Rab7L1 signaling pathway to inhibit phagosome-lysosome fusion. J Immunol 2018; 201:1421–1433
    [Google Scholar]
  82. MacLeod DA, Rhinn H, Kuwahara T, Zolin A, Di Paolo G et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron 2013; 77:425–439
    [Google Scholar]
  83. Hegymegi-Barakonyi B, Szekely R, Varga Z, Kiss R, Borbely G et al. Signalling inhibitors against Mycobacterium tuberculosis-early days of a new therapeutic concept in tuberculosis. Curr Med Chem 2008; 15:2760–2770
    [Google Scholar]
  84. Chen D, Ma S, He L, Yuan P, She Z et al. Sclerotiorin inhibits protein kinase G from Mycobacterium tuberculosis and impairs mycobacterial growth in macrophages. Tuberculosis 2017; 103:37–43
    [Google Scholar]
  85. Mesguiche V, Parsons RJ, Arris CE, Bentley J, Boyle FT et al. 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2. Bioorg Med Chem Lett 2003; 13:217–222
    [Google Scholar]
  86. Kidwai S, Bouzeyen R, Chakraborti S, Khare N, Das S et al. NU-6027 Inhibits Growth of Mycobacterium tuberculosis by Targeting Protein Kinase D and Protein Kinase G. Antimicrob Agents Chemother 2019; 63:
    [Google Scholar]
  87. Arris CE, Boyle FT, Calvert AH, Curtin NJ, Endicott JA et al. Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem 2000; 43:2797–2804
    [Google Scholar]
  88. Charrier J-D, Miller A, Kay DP, Brenchley G, Twin HC et al. Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors. J Med Chem 2011; 54:2341–2350
    [Google Scholar]
  89. Kanehiro Y, Tomioka H, Pieters J, Tatano Y, Kim H et al. Identification of novel mycobacterial inhibitors against mycobacterial protein kinase G. Front Microbiol 2018; 9:1517
    [Google Scholar]
  90. Zabludoff SD, Deng C, Grondine MR, Sheehy AM, Ashwell S et al. Azd7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Mol Cancer Ther 2008; 7:2955–2966
    [Google Scholar]
  91. Matsubara S, Li G, Takeda K, Loader JE, Pine P et al. Inhibition of spleen tyrosine kinase prevents mast cell activation and airway hyperresponsiveness. Am J Respir Crit Care Med 2006; 173:56–63
    [Google Scholar]
  92. Nguyen L, Walburger A, Houben E, Koul A, Muller S et al. Role of protein kinase G in growth and glutamine metabolism of Mycobacterium bovis BCG. J Bacteriol 2005; 187:5852–5856
    [Google Scholar]
  93. Rieck B, Degiacomi G, Zimmermann M, Cascioferro A, Boldrin F et al. PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis . PLoS Pathog 2017; 13:e1006399 [CrossRef][PubMed]
    [Google Scholar]
  94. Freeman BA, O’Donnell VB, Schopfer FJ. The discovery of nitro-fatty acids as products of metabolic and inflammatory reactions and mediators of adaptive cell signaling. Nitric oxide Biol Chem 2018; 77:106–111
    [Google Scholar]
  95. Gil M, Grana M, Schopfer FJ, Wagner T, Denicola A et al. Inhibition of Mycobacterium tuberculosis PknG by non-catalytic rubredoxin domain specific modification: reaction of an electrophilic nitro-fatty acid with the Fe-S center. Free Radic Biol Med 2013; 65:150–161
    [Google Scholar]
  96. Khan MZ, Kaur P, Nandicoori VK. Targeting the messengers: serine/threonine protein kinases as potential targets for antimycobacterial drug development. IUBMB Life 2018; 70:889–904
    [Google Scholar]
  97. Gagné F, Stress O. Oxidative stress. In Gagné FBT-BE. editor Biochemical Ecotoxicology Principals and Methods Oxford: Academic Press; 2014 pp 103–115
    [Google Scholar]
  98. Bielski BH, Arudi RL, Sutherland MW. A study of the reactivity of HO2/O2- with unsaturated fatty acids. J Biol Chem 1983; 258:4759–4761
    [Google Scholar]
  99. McCord JM, Fridovich I, dismutase S. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 1969; 244:6049–6055
    [Google Scholar]
  100. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988; 333:664–666
    [Google Scholar]
  101. Piacenza L, Trujillo M, Radi R. Reactive species and pathogen antioxidant networks during phagocytosis. J Exp Med 2019; 216:501–516 [CrossRef][PubMed]
    [Google Scholar]
  102. Rawat M, Av-Gay Y. Mycothiol-dependent proteins in actinomycetes. FEMS Microbiol Rev 2007; 31:278–292
    [Google Scholar]
  103. Pick N, Rawat M, Arad D, Lan J, Fan J et al. In vitro properties of antimicrobial bromotyrosine alkaloids. J Med Microbiol 2006; 55:407–415
    [Google Scholar]
  104. KSE U, Av-Gay Y. Mycothiol-dependent mycobacterial response to oxidative stress. FEBS Lett 2006; 580:2712–2716
    [Google Scholar]
  105. Newton GL, Av-Gay Y, Fahey RC. A novel mycothiol-dependent detoxification pathway in Mycobacteria involving mycothiol S -conjugate amidase. Biochemistry 2000; 39:10739–10746
    [Google Scholar]
  106. Sao Emani C, Williams MJ, Van Helden PD, Taylor MJC, Wiid IJ et al. Gamma-glutamylcysteine protects ergothioneine-deficient Mycobacterium tuberculosis mutants against oxidative and nitrosative stress. Biochem Biophys Res Commun 2018; 495:174–178
    [Google Scholar]
  107. Richard-Greenblatt M, Bach H, Adamson J, Pena-Diaz S, Wu L et al. Regulation of ergothioneine biosynthesis and its effect on Mycobacterium tuberculosis growth and infectivity. J Biol Chem 2015
    [Google Scholar]
  108. Sao Emani C, Gallant JL, Wiid IJ, Baker B. The role of low molecular weight thiols in Mycobacterium tuberculosis . Tuberculosis 2019; 116:44–55
    [Google Scholar]
  109. Vilchèze C, Av-Gay Y, Attarian R, Liu Z, Hazbón MH et al. Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis . Mol Microbiol 2008; 69:1316–1329
    [Google Scholar]
  110. Saini V, Cumming BM, Guidry L, Lamprecht DA, Adamson JH et al. Ergothioneine maintains redox and bioenergetic homeostasis essential for drug susceptibility and virulence of Mycobacterium tuberculosis . Cell Rep 2016; 0:
    [Google Scholar]
  111. Ta P, Buchmeier N, Newton GL, Rawat M, Fahey RC. Organic hydroperoxide resistance protein and ergothioneine compensate for loss of mycothiol in Mycobacterium smegmatis mutants. J Bacteriol 2011; 193:1981–1990
    [Google Scholar]
  112. Sao Emani C, Williams MJ, Wiid IJ, Baker B. The functional interplay of low molecular weight thiols in Mycobacterium tuberculosis . J Biomed Sci 2018; 25:55
    [Google Scholar]
  113. Braunstein M, Espinosa BJ, Chan J, Belisle JT R, Jacobs Jr W. SecA2 functions in the secretion of superoxide dismutase A and in the virulence of Mycobacterium tuberculosis . Mol Microbiol 2003; 48:453–464
    [Google Scholar]
  114. Nambi S, Long JE, Mishra BB, Baker R, Murphy KC et al. The Oxidative Stress Network of Mycobacterium tuberculosis Reveals Coordination between Radical Detoxification Systems. Cell Host Microbe 2015; 17:829–837
    [Google Scholar]
  115. Middlebrook G. Isoniazid-resistance and catalase activity of tubercle bacilli; a preliminary report. Am Rev Tuberc 1954; 69:471–472
    [Google Scholar]
  116. Timmins GS, Master S, Rusnak F, Deretic V. Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis . Antimicrob Agents Chemother 2004; 48:3006–3009
    [Google Scholar]
  117. Jaeger T. Peroxiredoxin systems in mycobacteria. Subcell Biochem 2007; 44:207–217
    [Google Scholar]
  118. Carabet LA, Guertin M, Lagüe P, Lamoureux G. Mechanism of the Nitric Oxide Dioxygenase Reaction of Mycobacterium tuberculosis Hemoglobin N. J Phys Chem B 2017; 121:8706–8718
    [Google Scholar]
  119. Jaeger T, Flohé L. The thiol-based redox networks of pathogens: unexploited targets in the search for new drugs. Biofactors 2006; 27:109–120
    [Google Scholar]
  120. Wong CF, Shin J, Subramanian Manimekalai MS, Saw WG, Yin Z et al. AhpC of the mycobacterial antioxidant defense system and its interaction with its reducing partner Thioredoxin-C. Sci Rep 2017; 7:5159
    [Google Scholar]
  121. Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 2000; 405:962–966
    [Google Scholar]
  122. Barry CE, Boshoff HIM, Dowd CS. Prospects for clinical introduction of nitroimidazole antibiotics for the treatment of tuberculosis. Curr Pharm Des 2004; 10:3239–3262
    [Google Scholar]
  123. Singh R, Manjunatha U, Boshoff HIM, YH H, Niyomrattanakit P et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 2008; 322:1392–1395
    [Google Scholar]
  124. Kim S-Y, Park Y-J, Kim W-I, Lee S-H, Ludgerus Chang C et al. Molecular analysis of isoniazid resistance in Mycobacterium tuberculosis isolates recovered from South Korea. Diagn Microbiol Infect Dis 2003; 47:497–502
    [Google Scholar]
  125. Piccaro G, Pietraforte D, Giannoni F, Mustazzolu A, Fattorini L. Rifampin induces hydroxyl radical formation in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2014; 58:7527–7533
    [Google Scholar]
  126. Betts JC, Lukey PT, Robb LC, McAdam RA, Duncan K. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol 2002; 43:717–731
    [Google Scholar]
  127. Gengenbacher M, SPS R, Pethe K, Dick T. Nutrient-starved, non-replicating Mycobacterium tuberculosis requires respiration, ATP synthase and isocitrate lyase for maintenance of ATP homeostasis and viability. Microbiology 2010; 156:81–87
    [Google Scholar]
  128. Jain P, Weinrick BC, Kalivoda EJ, Yang H, Munsamy V et al. Dual-reporter Mycobacteriophages (Φ2DRMs) reveal preexisting Mycobacterium tuberculosis persistent cells in human sputum. mBio 2016; 7:e01023–16
    [Google Scholar]
  129. Vilcheze C, Jacobs WRJ. The isoniazid paradigm of killing, resistance, and persistence in Mycobacterium tuberculosis . J Mol Biol 2019
    [Google Scholar]
  130. Vilchèze C, Hartman T, Weinrick B, Jain P, Weisbrod TR et al. Enhanced respiration prevents drug tolerance and drug resistance in Mycobacterium tuberculosis . Proc Natl Acad Sci 2017; 114:4495–4500
    [Google Scholar]
  131. Amaral EP, Conceição EL, Costa DL, Rocha MS, Marinho JM et al. N-acetyl-cysteine exhibits potent anti-mycobacterial activity in addition to its known anti-oxidative functions. BMC Microbiol 2016; 16:251
    [Google Scholar]
  132. Fialkow L, Wang Y, Downey GP. Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic Biol Med 2007; 42:153–164
    [Google Scholar]
  133. Al MH, Seo H, Kim S, Islam MI, Nam K-W et al. Thymoquinone (TQ) inhibits the replication of intracellular Mycobacterium tuberculosis in macrophages and modulates nitric oxide production. BMC Complement Altern Med 2017; 17:279
    [Google Scholar]
  134. Balazy M, Kaminski PM, Mao K, Tan J, Wolin MS. S-Nitroglutathione, a product of the reaction between peroxynitrite and glutathione that generates nitric oxide. J Biol Chem 1998; 273:32009–32015
    [Google Scholar]
  135. Venketaraman V, Talaue MT, Dayaram YK, Peteroy-Kelly MA, Bu W et al. Nitric oxide regulation of L-arginine uptake in murine and human macrophages. Tuberculosis 2003; 83:311–318
    [Google Scholar]
  136. Machelart A, Song O-R, Hoffmann E, Brodin P. Host-directed therapies offer novel opportunities for the fight against tuberculosis. Drug Discov Today 2017; 22:1250–1257
    [Google Scholar]
  137. Wipperman MF, Fitzgerald DW, Juste MAJ, Taur Y, Namasivayam S et al. Antibiotic treatment for tuberculosis induces a profound dysbiosis of the microbiome that persists long after therapy is completed. Sci Rep 2017; 7:10767
    [Google Scholar]
  138. Tiberi S, du Plessis N, Walzl G, Vjecha MJ, Rao M et al. Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies. Lancet Infect Dis 2018; 18:e183–198
    [Google Scholar]
  139. Kolloli A, Subbian S. Host-Directed therapeutic strategies for tuberculosis. Front Med 2017; 4:171
    [Google Scholar]
  140. Palucci I, Delogu G. Host directed therapies for tuberculosis: futures strategies for an ancient disease. Chemotherapy 2018; 63:172–180
    [Google Scholar]
  141. Sorrentino F, Gonzalez del Rio R, Zheng X, Presa Matilla J, Torres Gomez P et al. Development of an intracellular screen for new compounds able to inhibit Mycobacterium tuberculosis growth in human macrophages. Antimicrob Agents Chemother 2016; 60:640–645
    [Google Scholar]
  142. Richter A, Strauch A, Chao J, Ko M, Av-Gay Y. Screening of preselected libraries targeting Mycobacterium abscessus for drug discovery. Antimicrob Agents Chemother 2018; 62:e00828–18
    [Google Scholar]
  143. Tobin DM. Host-Directed therapies for tuberculosis. Cold Spring Harb Perspect Med 2015; 5:
    [Google Scholar]
  144. Stanley SA, Barczak AK, Silvis MR, Luo SS, Sogi K et al. Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth. PLOS Pathog 2014; 10:e1003946
    [Google Scholar]
  145. Korbee CJ, Heemskerk MT, Kocev D, van Strijen E, Rabiee O et al. Combined chemical genetics and data-driven bioinformatics approach identifies receptor tyrosine kinase inhibitors as host-directed antimicrobials. Nat Commun 2018; 9:358
    [Google Scholar]
  146. Zhou J, Xu R, Du X-Z, Zhou X-D, Li Q. Saxifragifolin D attenuates phagosome maturation arrest in Mycobacterium tuberculosis-infected macrophages via an AMPK and VPS34-dependent pathway. AMB Express 2017; 7:11 [CrossRef][PubMed]
    [Google Scholar]
  147. Crowle AJ, Douvas GS, May MH. Chlorpromazine: a drug potentially useful for treating mycobacterial infections. Chemotherapy 1992; 38:410–419
    [Google Scholar]
  148. Kristiansen JE, Dastidar SG, Palchoudhuri S, Roy DS, Das S et al. Phenothiazines as a solution for multidrug resistant tuberculosis: from the origin to present. Int Microbiol 2015; 18:1–12
    [Google Scholar]
  149. Juarez E, Carranza C, Sanchez G, Gonzalez M, Chavez J et al. Loperamide restricts intracellular growth of Mycobacterium tuberculosis in lung macrophages. Am J Respir Cell Mol Biol 2016; 55:837–847
    [Google Scholar]
  150. Bruns H, Stegelmann F, Fabri M, Dohner K, van Zandbergen G et al. Abelson tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages. J Immunol 2012; 189:4069–4078
    [Google Scholar]
  151. Napier RJ, Rafi W, Cheruvu M, Powell KR, Zaunbrecher MA et al. Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis. Cell Host Microbe 2011; 10:475–485
    [Google Scholar]
  152. Lachmandas E, Eckold C, Bohme J, Koeken V, Marzuki MB et al. Metformin alters human host responses to Mycobacterium tuberculosis in healthy subjects. J Infect Dis 2019
    [Google Scholar]
  153. Naicker N, Sigal A, Naidoo K. Metformin as host-directed therapy for TB treatment: scoping review. Front Microbiol 2020; 11:435
    [Google Scholar]
  154. Lougheed KEA, Taylor DL, Osborne SA, Bryans JS, Buxton RS. New anti-tuberculosis agents amongst known drugs. Tuberculosis 2009; 89:364–370
    [Google Scholar]
  155. Shapira T, Rankine-Wilson L, Chao JD, Pichler V, Rens C et al. High-content screening of eukaryotic kinase inhibitors identify CHK2 inhibitor activity against Mycobacterium tuberculosis . Front Microbiol 2020; 11:
    [Google Scholar]
  156. Festjens N, Vanden Berghe T, Vandenabeele P. Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta - Bioenerg 1757; 2006:1371–1387
    [Google Scholar]
  157. Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT. Pamps and DAMPs: signal’s that Spur autophagy and immunity. Immunol Rev 2012; 249:158–175 [CrossRef][PubMed]
    [Google Scholar]
  158. Fink SL, Apoptosis CBT. Pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 2005; 73:1907–1916
    [Google Scholar]
  159. Molloy A, Laochumroonvorapong P, Kaplan G. Apoptosis, but not necrosis, of infected monocytes is coupled with killing of intracellular Bacillus Calmette-Guérin. J Exp Med 1994; 180:1499–1509
    [Google Scholar]
  160. Butler RE, Brodin P, Jang J, Jang M-S, Robertson BD et al. The balance of apoptotic and necrotic cell death in Mycobacterium tuberculosis infected macrophages is not dependent on bacterial virulence. PLoS One 2012; 7:e47573
    [Google Scholar]
  161. Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M et al. Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 2001; 291:1544–1547
    [Google Scholar]
  162. Ashida H, Mimuro H, Ogawa M, Kobayashi T, Sanada T et al. Cell death and infection: a double-edged sword for host and pathogen survival. J Cell Biol 2011; 195:931 LP–942
    [Google Scholar]
  163. Yang H, Chen J, Chen Y, Jiang Y, Ge B et al. Sirtuin inhibits M. tuberculosis -induced apoptosis in macrophage through glycogen synthase kinase-3β. Arch Biochem Biophys 2020; 694:108612
    [Google Scholar]
  164. Friedrich A, Pechstein J, Berens C, Lührmann A. Modulation of host cell apoptotic pathways by intracellular pathogens. Curr Opin Microbiol 2017; 35:88–99
    [Google Scholar]
  165. Davis JM, Ramakrishnan L. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 2009; 136:37–49
    [Google Scholar]
  166. Behar SM, Martin CJ, Booty MG, Nishimura T, Zhao X et al. Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis . Mucosal Immunol 2011; 4:279–287
    [Google Scholar]
  167. Dobos KM, Spotts EA, Quinn FD, King CH. Necrosis of lung epithelial cells during infection with Mycobacterium tuberculosis is preceded by cell permeation. Infect Immun 2000; 68:6300–6310
    [Google Scholar]
  168. Watson RO, Manzanillo PS, Cox JS. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 2012; 150:803–815 [CrossRef][PubMed]
    [Google Scholar]
  169. Behar SM, Baehrecke EH. Tuberculosis: autophagy is not the answer. Nature 2015; 528:482–483
    [Google Scholar]
  170. Etna MP, Sinigaglia A, Grassi A, Giacomini E, Romagnoli A et al. Mycobacterium tuberculosis-induced miR-155 subverts autophagy by targeting Atg3 in human dendritic cells. PLoS Pathog 2018; 14:e1006790
    [Google Scholar]
  171. Fratazzi C, Arbeit RD, Carini C, Remold HG. Programmed cell death of Mycobacterium avium serovar 4-infected human macrophages prevents the mycobacteria from spreading and induces mycobacterial growth inhibition by freshly added, uninfected macrophages. J Immunol 1997; 158:4320–4327
    [Google Scholar]
  172. Hu W, Chan H, Lu L, Wong KT, Wong SH et al. Autophagy in intracellular bacterial infection. Semin Cell Dev Biol 2020; 101:41–50
    [Google Scholar]
  173. Singhal A, Jaiswal A, Arora VK, Prasad HK. Modulation of gamma interferon receptor 1 by Mycobacterium tuberculosis: a potential immune response evasive mechanism. Infect Immun. 2007/03/05 2007; 75:2500–2510
    [Google Scholar]
  174. Schiebler M, Brown K, Hegyi K, Newton SM, Renna M et al. Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. EMBO Mol Med 2015; 7:127–139
    [Google Scholar]
  175. Lee H-J, H-J K, Kim SH, Jung Y-J. Pasakbumin a controls the growth of Mycobacterium tuberculosis by enhancing the autophagy and production of antibacterial mediators in mouse macrophages. PLoS One 2019; 14:e0199799
    [Google Scholar]
  176. Bento CF, Empadinhas N, Mendes V. Autophagy in the fight against tuberculosis. DNA Cell Biol. 2015/01/21 2015; 34:228–242
    [Google Scholar]
  177. Cambier CJ, Falkow S, Ramakrishnan L. Host Evasion and Exploitation Schemes of Mycobacterium tuberculosis . Cell 2014; 159:1497–1509
    [Google Scholar]
  178. Lam A, Prabhu R, Gross CM, Riesenberg LA, Singh V et al. Role of apoptosis and autophagy in tuberculosis. Am J Physiol Lung Cell Mol Physiol 2017; 313:L218–229
    [Google Scholar]
  179. Queval CJ, Brosch R, Simeone R. The macrophage: a disputed fortress in the battle against Mycobacterium tuberculosis . Front Microbiol 2017; 8:2284
    [Google Scholar]
  180. Paik S, Kim JK, Chung C, E-K J. Autophagy: a new strategy for host-directed therapy of tuberculosis. Virulence 20181–12
    [Google Scholar]
  181. Kim J-J, Lee H-M, Shin D-M, Kim W, Yuk J-M et al. Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. Cell Host Microbe 2012; 11:457–468
    [Google Scholar]
  182. Wong D, Chao JD, Av-Gay Y. Mycobacterium tuberculosis-secreted phosphatases: from pathogenesis to targets for TB drug development. Trends Microbiol 2013; 21:100–109
    [Google Scholar]
  183. Welin A, Eklund D, Stendahl O, Lerm M. Human macrophages infected with a high burden of ESAT-6-expressing M. tuberculosis undergo caspase-1- and cathepsin B-independent necrosis. PLoS One 2011; 6:e20302
    [Google Scholar]
  184. Augenstreich J, Arbues A, Simeone R, Haanappel E, Wegener A et al. Esx-1 and phthiocerol dimycocerosates of Mycobacterium tuberculosis act in concert to cause phagosomal rupture and host cell apoptosis. Cell Microbiol 2017; 19:
    [Google Scholar]
  185. Singh B, Cocker D, Ryan H, Sloan DJ. Linezolid for drug-resistant pulmonary tuberculosis. Cochrane Database Syst Rev 2019; 3:CD012836 [CrossRef][PubMed]
    [Google Scholar]
  186. Singhal A, Jie L, Kumar P, Hong GS, Leow MK-S et al. Metformin as adjunct antituberculosis therapy. Sci Transl Med 2014; 6:
    [Google Scholar]
  187. Andersen P, Andersen AB, Sorensen AL, Nagai S. Recall of long-lived immunity to Mycobacterium tuberculosis infection in mice. J Immunol 1995; 154:3359–3372
    [Google Scholar]
  188. Brodin P, de Jonge MI, Majlessi L, Leclerc C, Nilges M et al. Functional analysis of early secreted antigenic target-6, the dominant T-cell antigen of Mycobacterium tuberculosis, reveals key residues involved in secretion, complex formation, virulence, and immunogenicity. J Biol Chem 2005; 280:33953–33959
    [Google Scholar]
  189. Houben D, Demangel C, van Ingen J, Perez J, Baldeón L et al. ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria. Cell Microbiol 2012; 14:1287–1298
    [Google Scholar]
  190. Venketaraman V, Dayaram YK, Amin AG, Ngo R, Green RM et al. Role of glutathione in macrophage control of mycobacteria. Infect Immun 2003; Apr 1;71:1864 LP–1871
    [Google Scholar]
  191. Pérez E, Samper S, Bordas Y, Guilhot C, Gicquel B et al. An essential role for phoP in Mycobacterium tuberculosis virulence. Mol Microbiol 2001; 41:179–187
    [Google Scholar]
  192. Wong D, Li W, Chao JD, Zhou P, Narula G et al. Protein tyrosine kinase, PtkA, is required for Mycobacterium tuberculosis growth in macrophages. Sci Rep 2018; 8:1–12
    [Google Scholar]
  193. Zulauf KE, Sullivan JT, Braunstein M. The SecA2 pathway of Mycobacterium tuberculosis exports effectors that work in concert to arrest phagosome and autophagosome maturation. PLOS Pathog 2018; 14:e1007011
    [Google Scholar]
  194. Edwards KM, Cynamon MH, Volari RKR, Hager CC, DeStefano MS et al. Iron-cofactored Superoxide Dismutase Inhibits Host Responses to Mycobacterium tuberculosis . Am J Respir Crit Care Med 2001; 164:2213–2219
    [Google Scholar]
  195. Kroesen VM, Rodríguez-Martínez P, García E, Rosales Y, Díaz J et al. A beneficial effect of low-dose aspirin in a murine model of active tuberculosis. Front Immunol 2018; 9:798
    [Google Scholar]
  196. Bezabeh T, Mowat MR, Jarolim L, Greenberg AH, Smith IC. Detection of drug-induced apoptosis and necrosis in human cervical carcinoma cells using 1H NMR spectroscopy. Cell Death Differ 2001; 8:219–224
    [Google Scholar]
  197. Juárez E, Carranza C, Sánchez G, González M, Chávez J et al. Loperamide restricts intracellular growth of Mycobacterium tuberculosis in lung macrophages. Am J Respir Cell Mol Biol 2016; 55:837–847
    [Google Scholar]
  198. KKY L, Zheng X, Forestieri R, Balgi AD, Nodwell M et al. Nitazoxanide stimulates autophagy and inhibits mTORC1 signaling and intracellular proliferation of Mycobacterium tuberculosis . PLoS Pathog 2012; 8:e1002691
    [Google Scholar]
  199. Williams DE, Dalisay DS, Chen J, Polishchuck EA, Patrick BO et al. Aminorifamycins and sporalactams produced in culture by a Micromonospora sp. isolated from a Northeastern-Pacific marine sediment are potent antibiotics. Org Lett 2017; 19:766–769
    [Google Scholar]
  200. Serebryakova VA, Urazova OI, Novitsky VV, Vengerovskii AI, Kononova TE et al. Effects of levofloxacin on blood lymphocyte apoptosis in patients with pulmonary tuberculosis: an in vitro study. Bull Exp Biol Med 2019; 168:109–112 [CrossRef]
    [Google Scholar]
  201. Floto RA, Sarkar S, Perlstein EO, Kampmann B, Schreiber SL et al. Small molecule enhancers of rapamycin-induced TOR inhibition promote autophagy, reduce toxicity in Huntington’s disease models and enhance killing of mycobacteria by macrophages. Autophagy 2007; 3:620–622 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.001041
Loading
/content/journal/micro/10.1099/mic.0.001041
Loading

Data & Media loading...

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