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Latent tuberculosis: interaction of virulence factors in Mycobacterium tuberculosis

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Abstract

Tuberculosis (TB) remains a prominent health concern worldwide. Besides extensive research and vaccinations available, attempts to control the pandemic are cumbersome due to the complex physiology of Mycobacterium tuberculosis (Mtb). Alongside the emergence of drug-resistant TB, latent TB has worsened the condition. The tubercle bacilli are unusually behaved and successful with its strategies to modulate genes to evade host immune system and persist within macrophages. Under latent/unfavorable conditions, Mtb conceals itself from immune system and modulates its genes. Among many intracellular modulated genes, important are those involved in cell entry, fatty acid degradation, mycolic acid synthesis, phagosome acidification inhibition, inhibition of phagosome-lysosome complex and chaperon protein modulation. Though the study on these genes date back to early times of TB, an insight on their inter-relation within and to newly evolved genes are still required. This review focuses on the findings and discussions on these genes, possible mechanism, credibility as target for novel drugs and repurposed drugs and their interaction that enables Mtb in survival, pathogenesis, resistance and latency.

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References

  1. Palomino JC, Martin A (2014) Drug resistance mechanisms in Mycobacterium tuberculosis. Antibiotics 3:317–340. https://doi.org/10.3390/antibiotics3030317

    Article  PubMed  PubMed Central  Google Scholar 

  2. World Health Organization (2019) WHO Global TB Report 2019

  3. Koul A, Arnoult E, Lounis N et al (2011) The challenge of new drug discovery for tuberculosis. Nature 469:483–490. https://doi.org/10.1038/nature09657

    Article  CAS  PubMed  Google Scholar 

  4. Pranger AD, van der Werf TS, Kosterink JGW, Alffenaar JWC (2019) The role of fluoroquinolones in the treatment of tuberculosis in 2019. Drugs 79:161–171. https://doi.org/10.1007/s40265-018-1043-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Peddireddy V, Doddam SN, Ahmed N (2017) Mycobacterial dormancy systems and host responses in tuberculosis. Front Immunol 8:1–19. https://doi.org/10.3389/fimmu.2017.00084

    Article  CAS  Google Scholar 

  6. Ehlers S, Schaible UE (2012) The granuloma in tuberculosis: dynamics of a host-pathogen collusion. Front Immunol 3:1–10. https://doi.org/10.3389/fimmu.2012.00411

    Article  Google Scholar 

  7. Ferraris DM, Miggiano R, Rossi F, Rizzi M (2018) Mycobacterium tuberculosis molecular determinants of infection, survival strategies, and vulnerable targets. Pathogens. https://doi.org/10.3390/pathogens7010017

    Article  PubMed  PubMed Central  Google Scholar 

  8. Meena LS, Rajni T (2010) Survival mechanisms of pathogenic Mycobacterium tuberculosis H37Rv. FEBS J 277:2416–2427. https://doi.org/10.1111/j.1742-4658.2010.07666.x

    Article  CAS  PubMed  Google Scholar 

  9. Zhai W, Wu F, Zhang Y et al (2019) The immune escape mechanisms of Mycobacterium tuberculosis. Int J Mol Sci. https://doi.org/10.3390/ijms20020340

    Article  PubMed  PubMed Central  Google Scholar 

  10. Beham AW, Puellmann K, Laird R et al (2011) A TNF-regulated recombinatorial macrophage immune receptor implicated in granuloma formation in tuberculosis. PLoS Pathog. https://doi.org/10.1371/journal.ppat.1002375

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ehrt S, Schnappinger D (2009) Mycobacterial survival strategies in the phagosome: Defense against host stresses. Cell Microbiol 11:1170–1178. https://doi.org/10.1111/j.1462-5822.2009.01335.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li J, Chai Q-Y, Zhang Y et al (2015) Mycobacterium tuberculosis Mce3E suppresses host innate immune responses by targeting ERK1/2 signaling. J Immunol 194:3756–3767. https://doi.org/10.4049/jimmunol.1402679

    Article  CAS  PubMed  Google Scholar 

  13. Qiang L, Wang J, Zhang Y et al (2019) Mycobacterium tuberculosis Mce2E suppresses the macrophage innate immune response and promotes epithelial cell proliferation. Cell Mol Immunol 16:380–391. https://doi.org/10.1038/s41423-018-0016-0

    Article  CAS  PubMed  Google Scholar 

  14. El-Shazly S, Ahmad S, Mustafa AS et al (2007) Internalization by HeLa cells of latex beads coated with mammalian cell entry (Mce) proteins encoded by the mce3 operon of Mycobacterium tuberculosis. J Med Microbiol 56:1145–1151. https://doi.org/10.1099/jmm.0.47095-0

    Article  CAS  PubMed  Google Scholar 

  15. Arruda S, Bomfim G, Knights R et al (1993) Cloning of an M. tuberculosis DNA fragment associated with entry and survival inside cells. Science (80-) 261:1454–1457. https://doi.org/10.1126/science.8367727

    Article  CAS  Google Scholar 

  16. Chai Q, Zhang Y, Liu CH (2018) Mycobacterium tuberculosis: an adaptable pathogen associated with multiple human diseases. Front Cell Infect Microbiol 8:1–15. https://doi.org/10.3389/fcimb.2018.00158

    Article  CAS  Google Scholar 

  17. Garcia-Perez BE, Castrejon-Jimenez NS, Luna-Herrer J (2012) The role of non-phagocytic cells in mycobacterial infections. Underst Tuberc. https://doi.org/10.5772/30335

    Article  Google Scholar 

  18. de La Paz M, Klepp L, Nuñez-García J et al (2009) Mce3R, a TetR-type transcriptional repressor, controls the expression of a regulon involved in lipid metabolism in Mycobacterium tuberculosis. Microbiology 155:2245–2255. https://doi.org/10.1099/mic.0.027086-0

    Article  CAS  Google Scholar 

  19. Joon M, Bhatia S, Pasricha R et al (2010) Functional analysis of an intergenic non-coding sequence within mce1 operon of M.tuberculosis. BMC Microbiol 10:128. https://doi.org/10.1186/1471-2180-10-128

  20. Zhang F, Xie JP (2011) Mammalian cell entry gene family of Mycobacterium tuberculosis. Mol Cell Biochem 352:1–10. https://doi.org/10.1007/s11010-011-0733-5

    Article  CAS  PubMed  Google Scholar 

  21. Casali N, White AM, Riley LW (2006) Regulation of the Mycobacterium tuberculosis mce1 operon. J Bacteriol 188:441–449. https://doi.org/10.1128/JB.188.2.441-449.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Singh P, Katoch VM, Mohanty KK, Chauhan DS (2016) Analysis of expression profile of mce operon genes (mce1, mce2, mce3 operon) in different Mycobacterium tuberculosis isolates at different growth phases. Indian J Med Res 143:487–494. https://doi.org/10.4103/0971-5916.184305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pandey AK, Sassetti CM (2008) Mycobacterial persistence requires the utilization of host cholesterol. Proc Natl Acad Sci USA 105:4376–4380. https://doi.org/10.1073/pnas.0711159105

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zhang Y, Li J, Li B et al (2018) Mycobacterium tuberculosis Mce3C promotes mycobacteria entry into macrophages through activation of β2 integrin-mediated signalling pathway. Cell Microbiol 20:1–16. https://doi.org/10.1111/cmi.12800

    Article  CAS  Google Scholar 

  25. Gioffré A, Infante E, Aguilar D et al (2005) Mutation in mce operons attenuates Mycobacterium tuberculosis virulence. Microbes Infect 7:325–334. https://doi.org/10.1016/j.micinf.2004.11.007

    Article  CAS  PubMed  Google Scholar 

  26. Haile Y, Caugant DA, Bjune G, Wiker HG (2002) Mycobacterium tuberculosis mammalian cell entry operon (mce) homologs in Mycobacterium other than tuberculosis (MOTT). FEMS Immunol Med Microbiol 33:125–132. https://doi.org/10.1016/S0928-8244(02)00302-4

    Article  CAS  PubMed  Google Scholar 

  27. Wipperman MF, Yang M, Thomas ST, Sampson NS (2013) Shrinking the fadE proteome of Mycobacterium tuberculosis: Insights into cholesterol metabolism through identification of an α2β2 heterotetrameric acyl coenzyme a dehydrogenase family. J Bacteriol 195:4331–4341. https://doi.org/10.1128/JB.00502-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nesbitt NM, Yang X, Fontán P et al (2010) A thiolase of Mycobacterium tuberculosis is required for virulence and production of androstenedione and androstadienedione from cholesterol. Infect Immun 78:275–282. https://doi.org/10.1128/IAI.00893-09

    Article  CAS  PubMed  Google Scholar 

  29. Casabon I, Crowe AM, Liu J, Eltis LD (2013) FadD3 is an acyl-CoA synthetase that initiates catabolism of cholesterol rings C and D in actinobacteria. Mol Microbiol 87:269–283. https://doi.org/10.1111/mmi.12095

    Article  CAS  PubMed  Google Scholar 

  30. Wipperman MF, Sampson NS, Suzanne TT (2014) Pathogen ’Roid Rage: cholesterol utilization by Mycobacterium tuberculosis. Crit Rev Biochem Mol Biol 49:269–293. https://doi.org/10.3109/10409238.2014.895700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Brzostek A, Pawelczyk J, Rumijowska-Galewicz A et al (2009) Mycobacterium tuberculosis is able to accumulate and utilize cholesterol. J Bacteriol 191:6584–6591. https://doi.org/10.1128/JB.00488-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Voskuil MI (2013) Mycobacterium tuberculosis cholesterol catabolism requires a new class of acyl coenzyme a dehydrogenase. J Bacteriol 195:4319–4321. https://doi.org/10.1128/JB.00867-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Takayama K, Wang C, Besra GS (2005) Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis genetic analysis of synthesis and processing of mycolic acid. Clin.microbiol.rev 18:81–101. https://doi.org/10.1128/CMR.18.1.81

  34. Sullivan et al (2006) High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis. ACS Chem Biol 1:43–53. https://doi.org/10.1021/cb0500042

    Article  CAS  PubMed  Google Scholar 

  35. Molle V, Gulten G, Vilchèze C et al (2010) Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis. Mol Microbiol 78:1591–1605. https://doi.org/10.1111/j.1365-2958.2010.07446.x

    Article  CAS  PubMed  Google Scholar 

  36. Wilson TM, de Lisle GW, Collins DM (1995) Effect of inhA and katG on isoniazid resistance and virulence of Mycobacterium bovis. Mol Microbiol 15:1009–1015. https://doi.org/10.1111/j.1365-2958.1995.tb02276.x

    Article  CAS  PubMed  Google Scholar 

  37. Kalokhe AS, Shafiq M, Lee JC et al (2013) Multidrug-resistant tuberculosis drug susceptibility and molecular diagnostic testing. Am J Med Sci 345:143–148. https://doi.org/10.1097/MAJ.0b013e31825d32c6

    Article  PubMed  PubMed Central  Google Scholar 

  38. Caws M, Dau QT, Phan MD et al (2007) PCR-restriction fragment length polymorphism for rapid, low-cost identification of isoniazid-resistant Mycobacterium tuberculosis. J Clin Microbiol 45:1789–1793. https://doi.org/10.1128/JCM.01960-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Torres JN, Paul LV, Rodwell TC et al (2015) Novel katG mutations causing isoniazid resistance in clinical M. Tuberculosis isolates. Emerg Microbes Infect 4:e42. https://doi.org/10.1038/emi.2015.42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Le HNT, Hijikata M, Maeda S et al (2019) Whole genome sequencing, analyses of drug resistance-conferring mutations, and correlation with transmission of Mycobacterium tuberculosis carrying katG-S315T in Hanoi. Vietnam Sci Rep 9:1–14. https://doi.org/10.1038/s41598-019-51812-7

    Article  CAS  Google Scholar 

  41. Isakova J, Sovkhozova N, Vinnikov D et al (2018) Mutations of rpoB, katG, inhA and ahp genes in rifampicin and isoniazid-resistant Mycobacterium tuberculosis in Kyrgyz Republic. BMC Microbiol. https://doi.org/10.1186/s12866-018-1168-x

    Article  PubMed  PubMed Central  Google Scholar 

  42. World Health Organization (2016) WHO Global TB Report 2016

  43. Lempens P, Meehan CJ, Vandelannoote K et al (2018) Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations. Sci Rep 8:1–9. https://doi.org/10.1038/s41598-018-21378-x

    Article  CAS  Google Scholar 

  44. Machado D, Couto I, Perdigão J et al (2012) Contribution of efflux to the emergence of isoniazid and multidrug resistance in Mycobacterium tuberculosis. PLoS ONE. https://doi.org/10.1371/journal.pone.0034538

    Article  PubMed  PubMed Central  Google Scholar 

  45. Unissa AN, Dusthackeer VNA, Kumar MP et al (2017) Variants of katG, inhA and nat genes are not associated with mutations in efflux pump genes (mmpL3 and mmpL7) in isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from India. Tuberculosis 107:144–148. https://doi.org/10.1016/j.tube.2017.07.014

    Article  CAS  PubMed  Google Scholar 

  46. Melly G, Purdy GE (2019) Mmpl proteins in physiology and pathogenesis of M. Tuberculosis. Microorganisms 7:1–16. https://doi.org/10.3390/microorganisms7030070

    Article  CAS  Google Scholar 

  47. Sandhu P, Akhter Y (2015) The internal gene duplication and interrupted coding sequences in the MmpL genes of Mycobacterium tuberculosis: towards understanding the multidrug transport in an evolutionary perspective. Int J Med Microbiol 305:413–423. https://doi.org/10.1016/j.ijmm.2015.03.005

    Article  CAS  PubMed  Google Scholar 

  48. Munir MK, Saqib M, Rehman S et al (2017) Type and frequency of mutations in katG and rpoB genes in multi-drug resistant strains of Mycobacterium Tuberculosis complex. Pak J Med Res 56:110–115

    Google Scholar 

  49. Sherman DR, Mdluli K, Hickey MJ et al (1999) AhpC, oxidative stress and drug resistance in Mycobacterium tuberculosis. BioFactors 10:211–217. https://doi.org/10.1002/biof.5520100219

    Article  CAS  PubMed  Google Scholar 

  50. Ramaswamy S, Musser JM (1998) Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis 79:3–29. https://doi.org/10.1054/tuld.1998.0002

    Article  CAS  PubMed  Google Scholar 

  51. Pagán-Ramos E, Master SS, Pritchett CL et al (2006) Molecular and physiological effects of mycobacterial oxyR inactivation. J Bacteriol 188:2674–2680. https://doi.org/10.1128/JB.188.7.2674-2680.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Franceschelli JJ, Belardinelli JM, Tong P et al (2018) A katG S315T or an ahpC promoter mutation mediate Mycobacterium tuberculosis resistance to 2-thiophen carboxylic acid hydrazide, an inhibitor resembling the anti-tubercular drugs Isoniazid and Ethionamide. Tuberculosis 112:69–78

    Article  CAS  PubMed  Google Scholar 

  53. Seifert M, Catanzaro D, Catanzaro A, Rodwell TC (2015) Genetic mutations associated with isoniazid resistance in Mycobacterium tuberculosis: a systematic review. PLoS ONE 10:1–13. https://doi.org/10.1371/journal.pone.0119628

    Article  CAS  Google Scholar 

  54. Hazbón MH, Brimacombe M, Del Valle MB et al (2006) Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 50:2640–2649. https://doi.org/10.1128/AAC.00112-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Georghiou SB, Seifert M, Catanzaro D et al (2016) Frequency and distribution of tuberculosis resistance-associated mutations between Mumbai, Moldova, and Eastern Cape. Antimicrob Agents Chemother 60:3994–4004. https://doi.org/10.1128/AAC.00222-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Haratiasl AA, Hamzelou G, Amini S et al (2020) Molecular identification of mutations conferring resistance to rifampin, isoniazid and pyrazinamide among Mycobacterium tuberculosis isolates from Iran. J Chemother 32:75–82. https://doi.org/10.1080/1120009X.2020.1716479

    Article  CAS  PubMed  Google Scholar 

  57. Liu L, Jiang F, Chen L et al (2018) The impact of combined gene mutations in inhA and ahpC genes on high levels of isoniazid resistance amongst katG non-315 in multidrug-resistant tuberculosis isolates from China. Emerg Microbes Infect. https://doi.org/10.1038/s41426-018-0184-0

    Article  PubMed  PubMed Central  Google Scholar 

  58. Li G, Zhang J, Jiang Y et al (2020) Cross-resistance of isoniazid, para-aminosalicylic acid and pasiniazid against isoniazid-resistant Mycobacterium tuberculosis isolates in China. J Glob Antimicrob Resist 20:275–281. https://doi.org/10.1016/j.jgar.2019.08.005

    Article  CAS  PubMed  Google Scholar 

  59. Purwantini E, Mukhopadhyay B (2013) Rv0132c of Mycobacterium tuberculosis encodes a coenzyme F 420-dependent hydroxymycolic acid dehydrogenase. PLoS ONE 8:4–12. https://doi.org/10.1371/journal.pone.0081985

    Article  CAS  Google Scholar 

  60. Marrakchi H, Lanéelle MA, Daffé M (2014) Mycolic acids: structures, biosynthesis, and beyond. Chem Biol 21:67–85. https://doi.org/10.1016/j.chembiol.2013.11.011

    Article  CAS  PubMed  Google Scholar 

  61. Glickman MS, Cahill SM, Jacobs WR (2001) The Mycobacterium tuberculosis cmaA2 gene encodes a mycolic acid trans- cyclopropane synthetase. J Biol Chem 276:2228–2233. https://doi.org/10.1074/jbc.C000652200

  62. Dubnau E, Chan J, Raynaud C et al (2000) Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Mol Microbiol 36:630–637. https://doi.org/10.1046/j.1365-2958.2000.01882.x

    Article  CAS  PubMed  Google Scholar 

  63. Rao V, Gao F, Chen B, Glickman MS (2006) Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses. J Clin Invest. https://doi.org/10.1172/JCI27335.1660

    Article  PubMed  PubMed Central  Google Scholar 

  64. Rao V, Fujiwara N, Porcelli SA, Glickman MS (2005) Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule. J Exp Med 201:535–543. https://doi.org/10.1084/jem.20041668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dutta NK, Karakousis PC (2014) Latent tuberculosis infection: myths, models, and molecular mechanisms. Microbiol Mol Biol Rev 78:343–371. https://doi.org/10.1128/mmbr.00010-14

    Article  PubMed  PubMed Central  Google Scholar 

  66. Sambandan D, Dao DN, Weinrick BC et al (2013) Keto-Mycolic acid-dependent pellicle formation confers tolerance to drug-sensitive Mycobacterium tuberculosis. MBio 4:1–10. https://doi.org/10.1128/mBio.00222-13

    Article  CAS  Google Scholar 

  67. Shan Chang DP, Guan XL (2021) Metabolic versatility of Mycobacterium tuberculosis during infection and dormancy. Metabolites 11:1–21. https://doi.org/10.3390/metabo11020088

    Article  CAS  Google Scholar 

  68. Côtes K, Bakala N’Goma JC, Dhouib R et al (2008) Lipolytic enzymes in Mycobacterium tuberculosis. Appl Microbiol Biotechnol 78:741–749. https://doi.org/10.1007/s00253-008-1397-2

    Article  CAS  PubMed  Google Scholar 

  69. Harth G, Clemens DL, Horwitz MA (1994) Glutamine synthetase of Mycobacterium tuberculosis: extracellular release and characterization of its enzymatic activity. Proc Natl Acad Sci U S A 91:9342–9346. https://doi.org/10.1073/pnas.91.20.9342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Raynaud C, Guilhot C, Rauzier J et al (2002) Phospholipases C are involved in the virulence of Mycobacterium tuberculosis. Mol Microbiol 45:203–217. https://doi.org/10.1046/j.1365-2958.2002.03009.x

    Article  CAS  PubMed  Google Scholar 

  71. Assis PA, Espíndola MS, Paula-Silva FW et al (2014) Mycobacterium tuberculosis expressing phospholipase C subverts PGE 2 synthesis and induces necrosis in alveolar macrophages. BMC Microbiol 14:1–10. https://doi.org/10.1186/1471-2180-14-128

    Article  CAS  Google Scholar 

  72. Le Chevalier F, Cascioferro A, Frigui W et al (2015) Revisiting the role of phospholipases C in virulence and the lifecycle of Mycobacterium tuberculosis. Sci Rep 5:1–13. https://doi.org/10.1038/srep16918

    Article  CAS  Google Scholar 

  73. Fisher AB, Jain M (2009) Phospholipases: degradation of phospholipids in membranes and emulsions. Encycl Life Sci. https://doi.org/10.1002/9780470015902.a0001394

  74. Villaseñor T, Madrid-Paulino E, Maldonado-Bravo R et al (2017) Activation of the Wnt pathway by Mycobacterium tuberculosis: a Wnt-Wnt situation. Front Immunol 8:1–16. https://doi.org/10.3389/fimmu.2017.00050

    Article  CAS  Google Scholar 

  75. Bakala N’Goma JC, Schué M, Carrière F et al (2010) Evidence for the cytotoxic effects of Mycobacterium tuberculosis phospholipase C towards macrophages. Biochim Biophys Acta - Mol Cell Biol Lipids 1801:1305–1313. https://doi.org/10.1016/j.bbalip.2010.08.007

    Article  CAS  Google Scholar 

  76. Kumari B (2020) Rv2037c, a stress induced conserved hypothetical protein of Mycobacterium tuberculosis, is a phospholipase: Role in cell wall modulation and intracellular survival. Biol Macromol 153:817–835. https://doi.org/10.1016/j.ijbiomac.2020.03.037

    Article  CAS  Google Scholar 

  77. Johansen KA, Gill RE, Vasil ML (1996) Biochemical and molecular analysis of phospholipase C and phospholipase D activity in Mycobacteria. Infect Immun 64:3259–3266. https://doi.org/10.1128/iai.64.8.3259-3266.1996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Talarico S, Durmaz R, Yang Z (2005) Insertion- and deletion-associated genetic diversity of Mycobacterium tuberculosis phospholipase C-encoding genes among 106 clinical isolates from Turkey. J Clin Microbiol 43:533–538. https://doi.org/10.1128/JCM.43.2.533-538.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lee HJ, Ko HJ, Song DK, Jung YJ (2018) Lysophosphatidylcholine promotes phagosome maturation and regulates inflammatory mediator production through the protein kinase a-phosphatidylinositol 3 kinase-p38 mitogen-activated protein kinase signaling pathway during Mycobacterium tuberculosis infect. Front Immunol. https://doi.org/10.3389/fimmu.2018.00920

    Article  PubMed  PubMed Central  Google Scholar 

  80. Paroha R, Chaurasiya SK, Chourasia R (2019) Phospholipase C-γ2 promotes intracellular survival of Mycobacteria. J Cell Biochem 120:5062–5071. https://doi.org/10.1002/jcb.27783

    Article  CAS  PubMed  Google Scholar 

  81. McKinney JD, Bentrup HZ, K, Muñoz-Elias EJ, et al (2000) Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406:735–738. https://doi.org/10.1038/35021074

    Article  CAS  PubMed  Google Scholar 

  82. Gengenbacher M, Rao SPS, Pethe K, Dick T (2010) Nutrient-starved, non-replicating Mycobacterium tuberculosis requires respiration, ATP synthase and isocitrate lyase for maintenance of ATP homeostasis and viability. Microbiology 156:81–87. https://doi.org/10.1099/mic.0.033084-0

    Article  CAS  PubMed  Google Scholar 

  83. López-Agudelo VA, Baena A, Ramirez-Malule H et al (2017) Metabolic adaptation of two in silico mutants of Mycobacterium tuberculosis during infection. BMC Syst Biol 11:1–18. https://doi.org/10.1186/s12918-017-0496-z

    Article  CAS  Google Scholar 

  84. Puckett S, Trujillo C, Wang Z et al (2017) Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 114:E2225–E2232. https://doi.org/10.1073/pnas.1617655114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bhusal RP, Bashiri G, Kwai BXC et al (2017) Targeting isocitrate lyase for the treatment of latent tuberculosis. Drug Discov Today 22:1008–1016. https://doi.org/10.1016/j.drudis.2017.04.012

    Article  CAS  PubMed  Google Scholar 

  86. Marrero J, Rhee KY, Schnappinger D et al (2010) Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection. Proc Natl Acad Sci USA 107:9819–9824. https://doi.org/10.1073/pnas.1000715107

    Article  PubMed  PubMed Central  Google Scholar 

  87. Sierra H, Cordova M, Chen CSJ, Rajadhyaksha M (2015) Confocal imaging-guided laser ablation of basal cell carcinomas: an ex vivo study. J Invest Dermatol 135:612–615. https://doi.org/10.1038/jid.2014.371

    Article  CAS  PubMed  Google Scholar 

  88. Nandakumar M, Nathan C, Rhee KY (2014) Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis. Nat Commun. https://doi.org/10.1038/ncomms5306

    Article  PubMed  Google Scholar 

  89. Eoh H, Rhee KY (2013) Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 110:6554–6559. https://doi.org/10.1073/pnas.1219375110

    Article  PubMed  PubMed Central  Google Scholar 

  90. Gutka HJ, Wang Y, Franzblau SG, Movahedzadeh F (2015) Glpx gene in mycobacterium tuberculosis is required for in vitro gluconeogenic growth and in-vivo survival. PLoS ONE 10:1–15. https://doi.org/10.1371/journal.pone.0138436

    Article  CAS  Google Scholar 

  91. Rohde KH, Abramovitch RB, Russell DG (2007) Mycobacterium tuberculosis invasion of macrophages: linking bacterial gene expression to environmental cues. Cell Host Microbe 2:352–364. https://doi.org/10.1016/j.chom.2007.09.006

    Article  CAS  PubMed  Google Scholar 

  92. Tripathi D, Kant S, Garg R, Bhatnagar R (2015) Low expression level of glnA1 accounts for absence of cell wall associated poly-L-glutamate/glutamine in Mycobacterium smegmatis. Biochem Biophys Res Commun 458:240–245. https://doi.org/10.1016/j.bbrc.2015.01.079

    Article  CAS  PubMed  Google Scholar 

  93. Russell DG (2001) Mycobacterium tuberculosis: here today, and here tomorrow. Nat Rev Mol Cell Biol 2:1–9. https://doi.org/10.1038/35085034

    Article  CAS  Google Scholar 

  94. Mehta R, Pearson JT, Mahajan S et al (2004) Adenylylation and catalytic properties of Mycobacterium tuberculosis glutamine synthetase expressed in Escherichia coli versus Mycobacteria. J Biol Chem 279:22477–22482. https://doi.org/10.1074/jbc.M401652200

    Article  CAS  PubMed  Google Scholar 

  95. Ponnan P, Gupta S, Chopra M et al (2013) 2D-QSAR, docking studies, and in silico ADMET prediction of polyphenolic acetates as substrates for protein acetyltransferase function of glutamine synthetase of Mycobacterium tuberculosis. ISRN Struct Biol 2013:1–12. https://doi.org/10.1155/2013/373516

    Article  Google Scholar 

  96. Harth G, Masleša-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. https://doi.org/10.1111/j.1365-2958.2005.04899.x

    Article  CAS  PubMed  Google Scholar 

  97. Rakovitsky N, Oz MB, Goldberg K et al (2018) The unexpected essentiality of glnA2 in Mycobacterium smegmatis is salvaged by overexpression of the global nitrogen regulator glnR, but not by L-, D-or iso-glutamine. Front Microbiol 9:1–8. https://doi.org/10.3389/fmicb.2018.02143

    Article  Google Scholar 

  98. 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. https://doi.org/10.1128/IAI.71.7.3927-3936.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Miller BH, Shinnick TM (2001) Identification of two Mycobacterium tuberculosis H37Rv ORFs involved in resistance to killing by human macrophages. BMC Microbiol 1:1–13. https://doi.org/10.1186/1471-2180-1-26

    Article  Google Scholar 

  100. Theron A, Roth RL, Hoppe H, et al (2017) Differential inhibition of adenylylated and deadenylylated forms of M. tuberculosis glutamine synthetase as a drug discovery platform. PLoS ONE. https://doi.org/10.1371/journal.pone.0185068

  101. Pashley CA, Brown AC, Robertson D, Parish T (2006) Identification of the Mycobacterium tuberculosis GlnE promoter and its response to nitrogen availability. Microbiology 152:2727–2734. https://doi.org/10.1099/mic.0.28942-0

    Article  CAS  PubMed  Google Scholar 

  102. Carroll P, Faray-Kele MC, Parish T (2011) Identifying vulnerable pathways in Mycobacterium tuberculosis by using a knockdown approach. Appl Environ Microbiol 77:5040–5043. https://doi.org/10.1128/AEM.02880-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Read R, Pashley CA, Smith D, Parish T (2007) The role of GlnD in ammonia assimilation in Mycobacterium tuberculosis. Tuberculosis 87:384–390

    Article  CAS  PubMed  Google Scholar 

  104. Wisedchaisri G, Holmes RK, Hol WGJ (2004) Crystal structure of an IdeR-DNA complex reveals a conformational change in activated IdeR for base-specific interactions. J Mol Biol 342:1155–1169. https://doi.org/10.1016/j.jmb.2004.07.083

    Article  CAS  PubMed  Google Scholar 

  105. Rodriguez GM, Smith I (2006) Identification of an ABC transporter required for iron acquisition and virulence in Mycobacterium tuberculosis. J Bacteriol 188:424–430. https://doi.org/10.1128/JB.188.2.424-430.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kochan I (1969) Mechanism of tuberculostasis in mammalian serum. I. Role of transferrin in human serum tuberculostasis. J Infect Dis 119:11–18. https://doi.org/10.1093/infdis/119.1.11

    Article  CAS  PubMed  Google Scholar 

  107. De Voss JJ, Rutter K, Schroeder BG et al (2000) The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc Natl Acad Sci USA 97:1252–1257. https://doi.org/10.1073/pnas.97.3.1252

    Article  PubMed  PubMed Central  Google Scholar 

  108. Sritharan M (2016) Iron Homeostasis in Mycobacterium tuberculosis: mechanistic insights into siderophore-mediated iron uptake. J Bacteriol 198:2399–2409. https://doi.org/10.1128/JB.00359-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yeruva VC, Duggirala S, Lakshmi V et al (2006) Identification and characterization of a major cell wall-associated iron-regulated envelope protein (Irep-28) in Mycobacterium tuberculosis. Clin Vaccine Immunol 13:1137–1142. https://doi.org/10.1128/CVI.00125-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ranjan S, Yellaboina S, Ranjan A (2006) IdeR in mycobacteria: from target recognition to physiological function. Crit Rev Microbiol 32:69–75. https://doi.org/10.1080/10408410600709768

    Article  CAS  PubMed  Google Scholar 

  111. LaMarca BBD, Zhu W, Arceneaux JEL et al (2004) Participation of fad and mbt Genes in synthesis of mycobactin in Mycobacterium smegmatis. J Bacteriol 186:374–382. https://doi.org/10.1128/JB.186.2.374-382.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Schmitt MP, Predich M, Doukhan L et al (1996) Erratum: Characterization of an iron-dependent regulatory protein (IdeR) of Mycobacterium tuberculosis as a functional homolog of the diphtheria toxin repressor (DtxR) from Corynebacterium diphtheriae (Infection and Immunity 63:11 (4289)). Infect Immun 64:681. https://doi.org/10.1128/iai.63.11.4284-4289.1995

    Article  CAS  Google Scholar 

  113. Chou CJ, Wisedchaisri G, Monfeli RR et al (2004) Functional studies of the Mycobacterium tuberculosis iron-dependent regulator. J Biol Chem 279:53554–53561. https://doi.org/10.1074/jbc.M407385200

    Article  CAS  PubMed  Google Scholar 

  114. Rodriguez GM (2006) Control of iron metabolism in Mycobacterium tuberculosis. Trends Microbiol 14:320–327. https://doi.org/10.1016/j.tim.2006.05.006

    Article  CAS  PubMed  Google Scholar 

  115. Pandey R, Rodriguez GM (2014) IdeR is required for iron homeostasis and virulence in Mycobacterium tuberculosis. Mol Microbiol 91:98–109. https://doi.org/10.1111/mmi.12441

    Article  CAS  PubMed  Google Scholar 

  116. Rohilla A, Khare G, Tyagi AK (2017) Virtual screening, pharmacophore development and structure based similarity search to identify inhibitors against IdeR, a transcription factor of Mycobacterium tuberculosis. Sci Rep 7:1–14. https://doi.org/10.1038/s41598-017-04748-9

    Article  CAS  Google Scholar 

  117. Salimizand H, Jamehdar SA, Nik LB, Sadeghian H (2017) Design of peptides interfering with iron-dependent regulator (IdeR) and evaluation of Mycobacterium tuberculosis growth inhibition. Iran J Basic Med Sci 20:722–728. https://doi.org/10.22038/ijbms.2017.8859

  118. Pohl E, Holmes RK, Hol WGJ (1999) Crystal structure of the iron-dependent regulator (IdeR) from Mycobacterium tuberculosis shows both metal binding sites fully occupied. J Mol Biol 285:1145–1156. https://doi.org/10.1006/jmbi.1998.2339

    Article  CAS  PubMed  Google Scholar 

  119. Manabe YC, Hatem CL, Kesavan AK et al (2005) Both Corynebacterium diphtheriae DtxR(E175K) and Mycobacterium tuberculosis IdeR(D177K) are dominant positive repressors of IdeR-regulated genes in M. tuberculosis. Infect Immun 73:5988–5994. https://doi.org/10.1128/IAI.73.9.5988-5994.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Prakash P, Yellaboina S, Ranjan A, Hasnain SE (2005) Computational prediction and experimental verification of novel IdeR binding sites in the upstream sequences of Mycobacterium tuberculosis open reading frames. Bioinformatics 21:2161–2166. https://doi.org/10.1093/bioinformatics/bti375

    Article  CAS  PubMed  Google Scholar 

  121. Siddiqui KF, Amir M, Agrewala JN (2011) Understanding the biology of 16 kDa antigen of Mycobacterium tuberculosis: scope in diagnosis, vaccine design and therapy. Crit Rev Microbiol 37:349–357. https://doi.org/10.3109/1040841X.2011.606425

    Article  CAS  PubMed  Google Scholar 

  122. Krishnan G, Roy U (2018) Prediction of recombinant Mycobacterium tuberculosis α-crystallin oligomer chaperone activity using polynomial graphs [version 1; peer review: 1 approved]. F1000Research 7:1–12. https://doi.org/10.12688/F1000RESEARCH.16328.1

  123. Jee B, Singh Y, Yadav R, Lang F (2018) Small heat shock protein 16.3 of Mycobacterium tuberculosis: after two decades of functional characterization. Cell Physiol Biochem 49:368–380. https://doi.org/10.1159/000492887

    Article  CAS  PubMed  Google Scholar 

  124. Sherman DR, Voskuil M, Schnappinger D et al (2001) Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding α-crystallin. Proc Natl Acad Sci U S A 98:7534–7539. https://doi.org/10.1073/pnas.121172498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. He H, Hovey R, Kane J et al (2020) MprAB is a stress-responsive two-component system that directly regulates expression of sigma factors SigB and SigE in Mycobacterium tuberculosis. J Bacteriol 202:2134–2143. https://doi.org/10.1128/JB.00443-20

    Article  Google Scholar 

  126. Pang X, Howard ST (2007) Regulation of the α-crystallin gene acr2 by the MprAB two-component system of Mycobacterium tuberculosis. J Bacteriol 189:6213–6221. https://doi.org/10.1128/JB.00492-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Vasudeva-Rao HM, McDonough KA (2008) Expression of the Mycobacterium tuberculosis acr-coregulated genes from the DevR (DosR) regulon is controlled by multiple levels of regulation. Infect Immun 76:2478–2489. https://doi.org/10.1128/IAI.01443-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Fontán P, Aris V, Ghanny S et al (2008) Global transcriptional profile of Mycobacterium tuberculosis during THP-1 human macrophage infection. Infect Immun 76:717–725. https://doi.org/10.1128/IAI.00974-07

    Article  CAS  PubMed  Google Scholar 

  129. Florczyk et al (2001) Identification and characterization of mycobacterial proteins differentially expressed understanding and shaking culture conditions, including Rv2623 from a novel class of putative ATP-binding proteins. Infect Immun 69:5777–5785. https://doi.org/10.1128/IAI.69.9.5777-5785.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Yuan Y, Crane DD, Simpson RM et al (1998) The 16-kDa α-crystallin (Acr) protein of Mycobacterium tuberculosis is required for growth in macrophages. Proc Natl Acad Sci USA 95:9578–9583. https://doi.org/10.1073/pnas.95.16.9578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Waddell S, Butcher P (2007) Microarray analysis of whole genome expression of intracellular Mycobacterium tuberculosis. Curr Mol Med 7:287–296. https://doi.org/10.2174/156652407780598548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Krishnan G, Roy U (2019) A new functional model for prediction of chaperone activity of the recombinant M. tb Acr ( -Crystallin) using insulin as substrate. Can J Infect Dis Med Microbiol 2019:8–10. https://doi.org/10.1155/2019/2532045

    Article  Google Scholar 

  133. Chetty S, Ramesh M, Singh-Pillay A, Soliman MES (2017) Recent advancements in the development of anti-tuberculosis drugs. Bioorganic Med Chem Lett 27:370–386. https://doi.org/10.1016/j.bmcl.2016.11.084

    Article  CAS  Google Scholar 

  134. Owens CP, Chim N, Graves AB et al (2013) The Mycobacterium tuberculosis secreted protein Rv0203 transfers heme to membrane proteins MmpL3 and MmpL11. J Biol Chem 288:21714–21728. https://doi.org/10.1074/jbc.M113.453076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Tahlan K, Wilson R, Kastrinsky DB et al (2012) SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother 56:1797–1809. https://doi.org/10.1128/AAC.05708-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Bhowruth V, Brown AK, Besra GS (2008) Synthesis and biological evaluation of NAS-21 and NAS-91 analogues as potential inhibitors of the mycobacterial FAS-II dehydratase enzyme Rv0636. Microbiology 154:1866–1875. https://doi.org/10.1099/mic.0.2008/017434-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Yuan T, Sampson NS (2018) Hit generation in TB drug discovery: from genome to granuloma. Chem Rev 118:1887–1916. https://doi.org/10.1021/acs.chemrev.7b00602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Moustafa GAI, Nojima S, Yamano Y et al (2013) Potent growth inhibitory activity of (±)-platencin towards multi-drug-resistant and extensively drug-resistant Mycobacterium tuberculosis. Medchemcomm 4:720–723. https://doi.org/10.1039/c3md00016h

    Article  CAS  Google Scholar 

  139. Betts JC, McLaren A, Lennon MG et al (2003) Signature gene expression profiles discriminate between isoniazid-, thiolactomycin-, and triclosan-treated Mycobacterium tuberculosis. Antimicrob Agents Chemother 47:2903–2913. https://doi.org/10.1128/AAC.47.9.2903-2913.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Defelipe LA, Osman F, Marti MA, Turjanski AG (2018) Structural and mechanistic comparison of the cyclopropane mycolic acid synthases (CMAS) protein family of Mycobacterium tuberculosis. Biochem Biophys Res Commun 498:288–295. https://doi.org/10.1016/j.bbrc.2017.08.119

    Article  CAS  PubMed  Google Scholar 

  141. Chen FC, Liao YC, Huang JM et al (2014) Pros and cons of the tuberculosis drugome approach—an empirical analysis. PLoS ONE. https://doi.org/10.1371/journal.pone.0100829

    Article  PubMed  PubMed Central  Google Scholar 

  142. Sassetti CM, Rubin EJ (2003) Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci USA 100:12989–12994. https://doi.org/10.1073/pnas.2134250100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank VIT, Vellore for extending their support.

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  1. School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India

    Sadhana Sundararajan & Rajiniraja Muniyan

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  1. Sadhana Sundararajan
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RM—Idea proposal and final manuscript review and approval. SS—Idea proposal, data collection and paper drafting.

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Sundararajan, S., Muniyan, R. Latent tuberculosis: interaction of virulence factors in Mycobacterium tuberculosis. Mol Biol Rep 48, 6181–6196 (2021). https://doi.org/10.1007/s11033-021-06611-7

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