Abstract
Tuberculosis (TB) is a pandemic disease caused by an obligate intracellular pathogen Mycobacterium tuberculosis (M.tb). The current TB therapy, Directly Observed Treatment Short-Course (DOTS), consists of the prolonged use of four antibiotics (Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol) that must be administered alone or in combination for at least 6 months to patients affected by drug-sensitive pulmonary TB. Although this therapy is efficient in eliminating M.tb, it has numerous side effects such as liver toxicity, poor compliance, and development of multidrug-resistant strains. Therefore, there is an urgent need for the development of new drug targets for the effective management of the disease and to also ensure the prevention of reinfection and reactivation of the disease. Here, in this chapter, we have discussed the presently available drugs and their mechanism of action for the treatment of TB as well as various other drugs, which have been repurposed and deployed for the treatment against drug-sensitive and drug-resistant TB.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
WHO Report, 2019
Schlesinger LS (1993) Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors. J Immunol 150:2920–2930
Fatima S, Kamble SS, Dwivedi VP et al (2020) Mycobacterium tuberculosis programs mesenchymal stem cells to establish dormancy and persistence. J Clin Invest 130(2):655–661
Stutz MD, Clark MP, Doerflinger M, Pellegrini M (2018) Mycobacterium tuberculosis: rewiring host cell signaling to promote infection. J Leukoc Biol 103(2):259–268
D’Ambrosio L, Centis R, Tiberi S et al (2017) Delamanid and bedaquiline to treat multidrug-resistant and extensively drug-resistant tuberculosis in children: a systematic review. J Thorac Dis 9(7):2093–2101
Smith I (2003) Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin Microbiol Rev 16(3):463–496
Bloom BR, Atun R, Cohen T et al (2017) Chapter 11: Tuberculosis. In: Holmes KK, Bertozzi S, Bloom BR et al (eds) Major infectious diseases, 3rd edn. The International Bank for Reconstruction and Development/The World Bank, Washington, DC
Guirado E, Schlesinger LS, Kaplan G (2013) Macrophages in tuberculosis: friend or foe. Semin Immunopathol 35(5):563–583
Ernst JD (1998) Macrophage receptors for Mycobacterium tuberculosis. Infect Immun 66(4):1277–1281
Sia JK, Rengarajan J (2019) Immunology of Mycobacterium tuberculosis infections. Microbiol Spectr 7(4). https://doi.org/10.1128/microbiolspec.GPP3-0022-2018
Zhai W, Wu F, Zhang Y, Fu Y, Liu Z (2019) The immune escape mechanisms of Mycobacterium Tuberculosis. Int J Mol Sci 20(2):340
Ndlovu H, Marakalala MJ (2016) Granulomas and inflammation: host-directed therapies for tuberculosis. Front Immunol 7:434
Cooper AM (2009) Cell-mediated immune responses in tuberculosis. Annu Rev Immunol 27:393–422
Fattorini L, Piccaro G, Mustazzolu A, Giannoni F (2013) Targeting dormant bacilli to fight tuberculosis. Mediterr J Hematol Infect Dis 5(1):e2013072
Sotgiu G, Centis R, D’ambrosio L, Migliori GB (2015) Tuberculosis treatment and drug regimens. Cold Spring Harb Perspect Med 5(5):a017822
Meena LS (2015) An overview to understand the role of PE_PGRS family proteins in Mycobacterium tuberculosis H37 Rv and their potential as new drug targets. Biotechnol Appl Biochem 62(2):145–153
Bachhawat N, Singh B (2007) Mycobacterial PE_PGRS proteins contain calcium-binding motifs with parallel beta-roll folds. Geno Prot Bioinfo 5:236–241
Tian C, Jian-Ping X (2010) Roles of PE_PGRS family in Mycobacterium tuberculosis pathogenesis and novel measures against tuberculosis. Microb Pathog 49:311–314
Koul A, Choidas A, Treder M et al (2000) Cloning and characterization of secretory tyrosine phosphatases of Mycobacterium tuberculosis. J Bacteriol 182(19):5425–5432
Bach H, Papavinasasundaram KG, Wong D, Hmama Z, Av-Gay Y (2008) Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human vacuolar protein sorting 33B. Cell Host Microbe 3(5):316–322
Beresford N, Patel S, Armstrong J, Szöor B, Fordham-Skelton AP, Tabernero L (2007) MptpB, a virulence factor from Mycobacterium tuberculosis, exhibits triple-specificity phosphatase activity. Biochem J 406(1):13–18
Koch MA, Waldmann H (2005) Protein structure similarity clustering and natural product structure as guiding principles in drug discovery. Drug Discov Today 10(7):471–483
Beresford NJ, Mulhearn D, Szczepankiewicz B et al (2009) Inhibition of MptpB phosphatase from Mycobacterium tuberculosis impairs mycobacterial survival in macrophages. J Antimicrob Chemother 63(5):928–936
Nören-Müller A, Reis-Corrêa I Jr, Prinz H et al (2006) Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis. Proc Natl Acad Sci U S A 103(28):10606–10611
Chow K, Ng D, Stokes R, Johnson P (1994) Protein tyrosine phosphorylation in Mycobacterium tuberculosis. FEMS Microbiol Lett 124:203–207
Walker JE, Saraste M, Runswick MJ, Gay NJ (1982) Distantly related sequences in the α- and β-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J 1(8):945–951
Bach H, Wong D, Av-Gay Y (2009) Mycobacterium tuberculosis PtkA is a novel protein tyrosine kinase whose substrate is PtpA. Biochem J 20(2):155–160
Sajid A, Arora G, Gupta M, Upadhyay S, Nandicoori VK, Singh Y (2011) Phosphorylation of Mycobacterium tuberculosis Ser/Thr phosphatase by PknA and PknB. PLoS One 6(3):e17871
Boitel B, Ortiz-LombardÃa M, Durán R et al (2003) PknB kinase activity is regulated by phosphorylation in two Thr residues and dephosphorylation by PstP, the cognate phospho-Ser/Thr phosphatase, in Mycobacterium tuberculosis. Mol Microbiol 49(6):1493–1508
Molle V, Brown AK, Besra GS, Cozzone AJ, Kremer L (2006) The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation. J Biol Chem 281(40):30094–30103
Wehenkel A, Bellinzoni M, Grana M, Duran R, Villarino A et al (2008) Mycobacterial Ser/Thr protein kinases and phosphatases: physiological roles and therapeutic potential. Biochim. Biophys Acta 1784:193–202
Fernandez P, Saint-Joanis B, Barilone N et al (2006) The Ser/Thr protein kinase PknB is essential for sustaining mycobacterial growth. J Bacteriol 188(22):7778–7784
Thakur M, Chaba R, Mondal AK, Chakraborti PK (2008) Interdomain interaction reconstitutes the functionality of PknA, a eukaryotic type Ser/Thr kinase from Mycobacterium tuberculosis. J Biol Chem 283(12):8023–8033
Thakur M, Chakraborti PK (2008) Ability of PknA, a mycobacterial eukaryotic-type serine/threonine kinase, to transphosphorylate MurD, a ligase involved in the process of peptidoglycan biosynthesis. Biochem J 415(1):27–33
Khan S, Nagarajan SN, Parikh A et al (2010) Phosphorylation of enoyl-acyl carrier protein reductase InhA impacts mycobacterial growth and survival. J Biol Chem 285(48):37860–37871
Parikh A, Verma SK, Khan S, Prakash B, Nandicoori VK (2009) PknB-mediated phosphorylation of a novel substrate, N-acetylglucosamine-1-phosphate uridyltransferase, modulates its acetyltransferase activity. J Mol Biol 386(2):451–464
Veyron-Churlet R, Molle V, Taylor RC et al (2009) The Mycobacterium tuberculosis β-ketoacyl-acyl carrier protein synthase III activity is inhibited by phosphorylation on a single threonine residue. J Biol Chem 284(10):6414–6424
Veyron-Churlet R, Zanella-Cléon I, Cohen-Gonsaud M, Molle V, Kremer L (2010) Phosphorylation of the Mycobacterium tuberculosis β-ketoacyl-acyl carrier protein reductase MabA regulates mycolic acid biosynthesis. J Biol Chem 285(17):12714–12725
Sureka K, Hossain T, Mukherjee P et al (2010) Novel role of phosphorylation-dependent interaction between FtsZ and FipA in mycobacterial cell division. PLoS One 5(1):e8590
Wehenkel A, Fernandez P, Bellinzoni M et al (2006) The structure of PknB in complex with mitoxantrone, an ATP-competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria. FEBS Lett 580(13):3018–3022
Hatzios SK, Baer CE, Rustad TR, Siegrist MS, Pang JM et al (2013) Osmosensory signaling in Mycobacterium tuberculosis mediated by a eukaryotic-like Ser/Thr protein kinase. Proc Natl Acad Sci 110:E5069–E5077
Greenstein AE, Echols N, Lombana TN, King DS, Alber T (2007) Allosteric activation by dimerization of the PknD receptor Ser/Thr protein kinase from Mycobacterium tuberculosis. J Biol Chem 282(15):11427–11435
Vanzembergh F, Peirs P, Lefevre P et al (2010) Effect of PstS sub-units or PknD deficiency on the survival of Mycobacterium tuberculosis. Tuberculosis (Edinb) 90(6):338–345
Be NA, Bishai WR, Jain SK (2012) Role of Mycobacterium tuberculosis pknD in the pathogenesis of central nervous system tuberculosis. BMC Microbiol 12:7
Jayakumar D, Jacobs WR Jr, Narayanan S (2008) Protein kinase E of Mycobacterium tuberculosis has a role in the nitric oxide stress response and apoptosis in a human macrophage model of infection. Cell Microbiol 10(2):365–374
Walburger A, Koul A, Ferrari G et al (2004) Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 304(5678):1800–1804
Houben EN, Walburger A, Ferrari G et al (2009) Differential expression of a virulence factor in pathogenic and non-pathogenic mycobacteria. Mol Microbiol 72(1):41–52
Av-Gay Y, Everett M (2000) The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis. Trends Microbiol 8(5):238–244
Scherr N, Honnappa S, Kunz G et al (2007) Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis. Proc Natl Acad Sci 104(29):12151–12156
Tiwari D, Singh RK, Goswami K, Verma SK, Prakash B, Nandicoori VK (2009) Key residues in Mycobacterium tuberculosis protein kinase G play a role in regulating kinase activity and survival in the host. J Biol Chem 284(40):27467–27479
Scherr N, Müller P, Perisa D, Combaluzier B, Jenö P, Pieters J (2009) Survival of pathogenic mycobacteria in macrophages is mediated through autophosphorylation of protein kinase G. J Bacteriol 191(14):4546–4554
Santhi N, Aishwarya S (2011) Insights from the molecular docking of withanolide derivatives to the target protein PknG from Mycobacterium tuberculosis. Bioinformation 7(1):1–4
Molle V, Reynolds RC, Alderwick LJ et al (2008) EmbR2, a structural homologue of EmbR, inhibits the Mycobacterium tuberculosis kinase/substrate pair PknH/EmbR. Biochem J 410(2):309–317
Malhotra V, Arteaga-Cortés LT, Clay G, Clark-Curtiss JE (2010) Mycobacterium tuberculosis protein kinase K confers survival advantage during early infection in mice and regulates growth in culture and during persistent infection: implications for immune modulation. Microbiology (Reading, Engl) 156(9):2829–2841
Napier RJ, Rafi W, Cheruvu M et al (2011) Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis. Cell Host Microbe 10(5):475–485
Saleh MT, Belisle JT (2000) Secretion of an acid phosphatase (SapM) by Mycobacterium tuberculosis that is similar to eukaryotic acid phosphatases. J Bacteriol 182(23):6850–6853
Vergne I, Chua J, Lee HH, Lucas M, Belisle J, Deretic V (2005) Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 102(11):4033–4038
Vergne I et al (2005) Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 102:4033–4038
Brodin P, Rosenkrands I, Andersen P, Cole ST, Brosch R (2004) ESAT-6 proteins: protective antigens and virulence factors? Trends Microbiol 12(11):500–508
van der Wel N, Hava D, Houben D et al (2007) M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129(7):1287–1298
Volkman HE, Pozos TC, Zheng J, Davis JM, Rawls JF, Ramakrishnan L (2010) Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science 327(5964):466–469
Sullivan JT, Young EF, McCann JR, Braunstein M (2012) The Mycobacterium tuberculosis SecA2 system subverts phagosome maturation to promote growth in macrophages. Infect Immun 80(3):996–1006
Dilks K, Rose RW, Hartmann E, Pohlschröder M (2003) Prokaryotic utilization of the twin-arginine translocation pathway: a genomic survey. J Bacteriol 185(4):1478–1483
Becker SH, Jastrab JB, Dhabaria A, Chaton CT, Rush JS, Korotkov KV, Ueberheide B, Darwin KH (2019) The Mycobacterium tuberculosis pup-proteasome system regulates nitrate metabolism through an essential protein quality control pathway. Proc Natl Acad Sci U S A 116(8):3202–3210
Cromm PM, Crews CM (2017) The proteasome in modern drug discovery: second life of a highly valuable drug target. ACS Cent Sci 3(8):830–838
Lin G, Li D, de Carvalho LP et al (2009) Inhibitors selective for mycobacterial versus human proteasomes. Nature 461(7264):621–626
Cheng Y, Pieters J (2010) Novel proteasome inhibitors as potential drugs to combat tuberculosis. J Mol Cell Biol 2(4):173–175
Shenoy AR, Visweswariah SS (2006) New messages from old messengers: cAMP and mycobacteria. Trends Microbiol 14(12):543–550
Agarwal N, Lamichhane G, Gupta R, Nolan S, Bishai WR (2009) Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase. Nature 460(7251):98–102
Rohde K, Yates RM, Purdy GE, Russell DG (2007) Mycobacterium tuberculosis and the environment within the phagosome. Immunol Rev 219:37–54
Pieters J (2008) Mycobacterium tuberculosis and the macrophage: maintaining a balance. Cell Host Microbe 3:399–407
Warner DF, Mizrahi V (2007) The survival kit of Mycobacterium tuberculosis. Nat Med 13:282–284
Eckert C, Hammesfahr B, Kollmar M (2011) A holistic phylogeny of the coronin gene family reveals an ancient origin of the tandem-coronin, defines a new subfamily, and predicts protein function. BMC Evol Biol 11:268
Pieters J, Muller P, Jayachandran R (2013) On guard: coronin proteins in innate and adaptive immunity. Nat Rev Immunol 13:510–518
Jayachandran R, Sundaramurthy V, Combaluzier B, Mueller P, Korf H, Huygen K et al (2007) Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin. Cell 130:37–50
Neer EJ, Schmidt CJ, Nambudripad R, Smith TF (1994) The ancient regulatory-protein family of WD-repeat proteins. Nature 371(6495):297–300
Ferrari G, Langen H, Naito M, Pieters J (1999) A coat protein on phagosomes involved in the intracellular survival of mycobacteria. Cell 97:435–447
Winslow MM, Neilson JR, Crabtree GR (2003) Calcium signalling in lymphocytes. Curr Opin Immunol 15(3):299–307
Wiley JS, Sluyter R, Gu BJ, Stokes L, Fuller SJ (2011) The human P2X7 receptor and its role in innate immunity. Tissue Antigens 78:321e32
Song L, Cui R, Yang Y, Wu X (2015) Role of calcium channels in cellular antituberculosis effects: potential of voltage-gated calcium-channel blockers in tuberculosis therapy. J Microbiol Immunol Infect 48(5):471–476
Gupta S, Salam N, Srivastava V, Singla R, Behera D, Khayyam KU et al (2009) Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis. PLoS One 4:e5305
Lammas DA, Stober C, Harvey CJ, Kendrick N, Panchalingam S, Kumararatne DS (1997) ATP-induced killing of mycobacteria by human macrophages is mediated by purinergic P2Z(P2X7) receptors. Immunity 7:433e44
Adams KN, Szumowski JD, Ramakrishnan L (2014) Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple antitubercular drugs. J Infect Dis 210:456e66
Sharma D, Tiwari BK, Mehto S et al (2016) Suppression of protective responses upon activation of L-type voltage gated calcium channel in macrophages during Mycobacterium bovis BCG infection. PLoS One 11(10):e0163845
Gupta S, Tyagi S, Almeida DV, Maiga MC, Ammerman NC, Bishai WR (2013) Acceleration of tuberculosis treatment by adjunctive therapy with verapamil as an efflux inhibitor. Am J Respir Crit Care Med 188:600e7
Chen C, Gardete S, Jansen RS et al (2018) Verapamil Targets Membrane Energetics in Mycobacterium tuberculosis. Antimicrob Agents Chemother 62(5):e02107–e02117
Caseley EA, Muench SP, Roger S, Mao HJ, Baldwin SA, Jiang LH (2014) Non-synonymous single nucleotide polymorphisms in the P2X receptor genes: association with diseases, impact on receptor functions and potential use as diagnosis biomarkers. Int J Mol Sci 15(8):13344–13371
Tominaga K, Yoshimoto T, Torigoe K, Kurimoto M, Matsui K, Hada T et al (2000) IL-12 synergizes with IL-18 or IL-1beta for IFN-gamma production from human T cells. Int Immunol 12:151–160
Savio LEB, de Andrade Mello P, da Silva CG, Coutinho-Silva R (2018) The P2X7 receptor in inflammatory diseases: angel or demon? Front Pharmacol 9:52
Carrithers LM, Hulseberg P, Sandor M, Carrithers MD (2011) The human macrophage sodium channel NaV1.5 regulates mycobacteria processing through organelle polarization and localized calcium oscillations. FEMS Immunol Med Microbiol 63(3):319–327
Wulff H, Castle NA, Pardo LA (2009) Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov 8(12):982–1001
Gilly M, Wall R (1992) The IRG-47 gene is IFN-γ induced in B cells and encodes a protein with GTP-binding motifs. J Immunol 148(10):3275–3281
Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V (2004) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119(6):753–766
Singh SB, Ornatowski W, Vergne I et al (2010) Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria. Nat Cell Biol 12(12):1154–1165
Petkova DS, Viret C, Faure M (2013) IRGM in autophagy and viral infections. Front Immunol 3:426
McCarroll SA, Huett A, Kuballa P, Chilewski SD, Landry A, Goyette P et al (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat Genet 40:1107–1112
Lapaquette P, Glasser AL, Huett A, Xavier RJ, Darfeuille-Michaud A (2010) Crohn’s disease-associated adherent-invasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly. Cell Microbiol 12(1):99–113
Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V et al (2011) A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat Genet 43:242–245
Gregoire IP, Rabourdin-Combe C, Faure M (2012) Autophagy and RNA virus interactomes reveal IRGM as a common target. Autophagy 8:1136–1137
Matsuzawa T, Kim BH, Shenoy AR, Kamitani S, Miyake M, Macmicking JD (2012) IFN-gamma elicits macrophage autophagy via the p38 MAPK signaling pathway. J Immunol 189:813–818
MacMicking JD, Taylor GA, McKinney JD (2003) Immune control of tuberculosis by IFN-γ-inducible LRG-47. Science 302(5645):654–659
Lee YV, Wahab HA, Choong YS (2015) Potential inhibitors for isocitrate lyase of Mycobacterium tuberculosis and non-M. tuberculosis: a summary. Biomed Res Int 2015:895453
Bishai W (2000) Lipid lunch for persistent pathogen. Nature 406(6797):683–685
Muñoz-ElÃas EJ, McKinney JD (2005) Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat Med 11(6):638–644
Stamm CE, Collins AC, Shiloh MU (2015) Sensing of Mycobacterium tuberculosis and consequences to both host and bacillus. Immunol Rev 264(1):204–219
Basu J, Shin DM, Jo EK (2012) Mycobacterial signaling through toll-like receptors. Front Cell Infect Microbiol 2:145
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Fatima, S., Bhardwaj, B., Dwivedi, V.P. (2021). Targeting Host and Bacterial Signaling Pathways in Tuberculosis: An Effective Strategy for the Development of Novel Anti-tubercular Therapies. In: Dua, K., Löbenberg, R., Malheiros Luzo, Â.C., Shukla, S., Satija, S. (eds) Targeting Cellular Signalling Pathways in Lung Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-33-6827-9_16
Download citation
DOI: https://doi.org/10.1007/978-981-33-6827-9_16
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-33-6826-2
Online ISBN: 978-981-33-6827-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)