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Cell envelope lipids in the pathophysiology of Mycobacterium tuberculosis

    Parul Singh

    Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting & Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad, 500 039, India

    Graduate Studies, Manipal Academy of Higher Education, Manipal, Karnataka, 576 104, India

    Authors contributed equally

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    ,
    Nagender Rao Rameshwaram

    Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting & Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad, 500 039, India

    Authors contributed equally

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    ,
    Sudip Ghosh

    Molecular Biology Division, National Institute of Nutrition (ICMR), Jamai-Osmania PO, Hyderabad, 500 007, India

    &
    Sangita Mukhopadhyay

    *Author for correspondence: Tel.: +91 40 2721 6000; Fax: +91 40 272106006;

    E-mail Address: sangita@cdfd.org.in

    Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting & Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad, 500 039, India

    Published Online:https://doi.org/10.2217/fmb-2017-0135

    Mycobacterium tuberculosis is an intracellular bacterium that persists and replicates inside macrophages. The bacterium possesses an unusual lipid-rich cell envelope that provides a hydrophobic impermeable barrier against many environmental stressors and allows it to survive extremely hostile intracellular surroundings. Since the lipid-rich envelope is crucial for M. tuberculosis virulence, the components of the cell wall lipid biogenesis pathways constitute an attractive target for the development of vaccines and antimycobacterial chemotherapeutics. In this review, we provide a detailed description of the mycobacterial cell envelope lipid components and their contributions to the physiology and pathogenicity of mycobacteria. We also discussed the current status of the antimycobacterial drugs that target biosynthesis, export and regulation of cell envelope lipids.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Smith I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin. Microbiol. Rev. 16(3), 463–496 (2003).
    • 2 World Health Organization. Global tuberculosis report – 2016. WHO, Geneva. http://apps.who.int/iris/bitstream/10665/137094/1/9789241564809_eng.pdf.• Gives the most recent account of the incidence of Mycobacterium tuberculosis infection and progress made worldwide.
    • 3 World Health Organization. Latent TB infection fact sheet (2014). www.who.int/tb/challenges/ltbi_factsheet_2014.pdf?ua=1.
    • 4 Houben RM, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med. 13(10), e1002152 (2016).
    • 5 Mukhopadhyay S, Nair S, Ghosh S. Pathogenesis in tuberculosis: transcriptomic approaches to unraveling virulence mechanisms and finding new drug targets. FEMS Microbiol. Rev. 36(2), 463–485 (2012).
    • 6 Pieters J. Mycobacterium tuberculosis and the macrophage: maintaining a balance. Cell Host Microbe. 3(6), 399–407 (2008).
    • 7 Goren MB. Mycobacterial lipids: selected topics. Bacteriol. Rev. 36(1), 33–64 (1972).
    • 8 Glickman MS, Jacobs WR Jr. Microbial pathogenesis of Mycobacterium tuberculosis: dawn of a discipline. Cell 104(4), 477–485 (2001).
    • 9 Jarlier V, Nikaido H. Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS Microbiol. Lett. 123(1–2), 11–18 (1994).
    • 10 Rousseau C, Winter N, Pivert E et al. Production of phthiocerol dimycocerosates protects Mycobacterium tuberculosis from the cidal activity of reactive nitrogen intermediates produced by macrophages and modulates the early immune response to infection. Cell Microbiol. 6(3), 277–287 (2004).
    • 11 Korf J, Stoltz A, Verschoor J, De Baetselier P, Grooten J. The Mycobacterium tuberculosis cell wall component mycolic acid elicits pathogen-associated host innate immune responses. Eur. J. Immunol. 35(3), 890–900 (2005).
    • 12 Ernst JD. Macrophage receptors for Mycobacterium tuberculosis. Infect. Immun. 66(4), 1277–1281 (1998).
    • 13 Tailleux L, Schwartz O, Herrmann JL et al. DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J. Exp. Med. 197(1), 121–127 (2003).
    • 14 Villeneuve C, Gilleron M, Maridonneau-Parini I et al. Mycobacteria use their surface-exposed glycolipids to infect human macrophages through a receptor-dependent process. J. Lipid. Res. 46(3), 475–483 (2005).
    • 15 Astarie-Dequeker C, Le Guyader L, Malaga W et al. Phthiocerol dimycocerosates of M. tuberculosis participate in macrophage invasion by inducing changes in the organization of plasma membrane lipids. PLoS Pathog. 5(2), e1000289 (2009).
    • 16 Hegde P, Kaveri SV, Bayry J. Toll-like receptor-2 ligand lipomannan from Mycobacterium tuberculosis does not stimulate inflammatory cytokines in dendritic cells. AIDS 26(9), 1182–1184 (2012).
    • 17 Johansson U, Ivanyi J, Londei M. Inhibition of IL-12 production in human dendritic cells matured in the presence of Bacillus Calmette-Guérin or lipoarabinomannan. Immunol. Lett. 77(1), 63–66 (2001).
    • 18 Nigou J, Zelle-Rieser C, Gilleron M et al. Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor. J. Immunol. 166(12), 7477–7485 (2001).
    • 19 Hoffmann C, Leis A, Niederweis M et al. Disclosure of the mycobacterial outer membrane: cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc. Natl Acad. Sci. USA 105(10), 3963–3967 (2008).
    • 20 Zuber B, Chami M, Houssin C et al. Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. J. Bacteriol. 190(16), 5672–5680 (2008).
    • 21 Pitarque S, Larrouy-Maumus G, Payré B et al. The immunomodulatory lipoglycans, lipoarabinomannan and lipomannan, are exposed at the mycobacterial cell surface. Tuberculosis (Edinb). 88(6), 560–565 (2008).
    • 22 Forrellad MA, Klepp LI, Gioffré A et al. Virulence factors of the Mycobacterium tuberculosis complex. Virulence 4(1), 3–66 (2013).
    • 23 Fukuda T, Matsumura T, Ato M et al. Critical roles for lipomannan and lipoarabinomannan in cell wall integrity of mycobacteria and pathogenesis of tuberculosis. MBio 4(1), e00472-12 (2013).
    • 24 Ehrt S, Schnappinger D. Mycobacterial survival strategies in the phagosome: defence against host stresses. Cell Microbiol. 11(8), 1170–1178 (2009).
    • 25 Matsuhashi M. Biosynthesis in the bacterial cell wall. Tanpakushitsu Kakusan Koso. 11(10), 875–886 (1966).
    • 26 Jackson M, McNeil MR, Brennan PJ. Progress in targeting cell envelope biogenesis in Mycobacterium tuberculosis. Future Microbiol. 8(7), 855–875 (2013).
    • 27 Marrakchi H, Lanéelle MA, Daffé M. Mycolic acids: structures, biosynthesis, and beyond. Chem. Biol. 21(1), 67–85 (2014).
    • 28 Besra GS, McNeil MR, Khoo KH et al. Trehalose-containing lipooligosaccharides of Mycobacterium gordonae: presence of a mono-O-methyltetra-O-acyltrehalose “core” and branching in the oligosaccharide backbone. Biochemistry 32(47), 12705–12714 (1993).
    • 29 Besra GS, Khoo KH, Belisle JT et al. New pyruvylated, glycosylated acyltrehaloses from Mycobacterium smegmatis strains, and their implications for phage resistance in mycobacteria. Carbohydr. Res. 251, 99–114 (1994).
    • 30 Besra GS, Gurcha SS, Khoo KH et al. Characterization of the specific antigenicity of representatives of M. senegalense and related bacteria. Zentralbl. Bakteriol. 281(4), 415–432 (1994).
    • 31 van der Woude AD, Sarkar D, Bhatt A et al. Unexpected link between lipooligosaccharide biosynthesis and surface protein release in Mycobacterium marinum. J. Biol. Chem. 287(24), 20417–20429 (2012).
    • 32 Chen JM, German GJ, Alexander DC et al. Roles of Lsr2 in colony morphology and biofilm formation of Mycobacterium smegmatis. J. Bacteriol. 188(2), 633–641 (2006).
    • 33 Brennan PJ, Nikaido H. The envelope of mycobacteria. Annu. Rev. Biochem. 64, 29–63 (1995).
    • 34 Niederweis M. Mycobacterial porins – new channel proteins in unique outer membranes. Mol. Microbiol. 49(5), 1167–1177 (2003).
    • 35 Trias J, Jarlier V, Benz R. Porins in the cell wall of mycobacteria. Science 258(5087), 1479–1481 (1992).
    • 36 Yuan Y, Lee RE, Besra GS et al. Identification of a gene involved in the biosynthesis of cyclopropanated mycolic acids in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 92(14), 6630–6634 (1995).
    • 37 Senaratne RH, Mobasheri H, Papavinasasundaram KG et al. Expression of a gene for a porin-like protein of the OmpA family from Mycobacterium tuberculosis H37Rv. J. Bacteriol. 180(14), 3541–3547 (1998).
    • 38 Kartmann B, Stenger S, Niederweis M. Porins in the cell wall of Mycobacterium tuberculosis. J. Bacteriol. 181(20), 6543–6546 (1999).
    • 39 Lichtinger T, Burkovski A, Niederweis M et al. Biochemical and biophysical characterization of the cell wall porin of Corynebacterium glutamicum: the channel is formed by a low molecular mass polypeptide. Biochemistry 37(43), 15024–15032 (1998).
    • 40 Speer A, Rowland JL, Haeili M et al. Porins increase copper susceptibility of Mycobacterium tuberculosis. J. Bacteriol. 195(22), 5133–5140 (2013).
    • 41 Kremer L, Besra GS. A waxy tale, by Mycobacterium tuberculosis. In: Tuberculosis and the Tubercle Bacillus. Cole S, Eisenach K, McMurray D, Jacobs WR Jr (Eds). ASM Press, Washington, D.C. USA, 287–305 (2005).
    • 42 Ratnam S, Chandrasekhar S. The pathogenicity of spheroplasts of Mycobacterium tuberculosis. Am. Rev. Respir. Dis. 114(3), 549–554 (1976).
    • 43 Cunningham AF, Spreadbury CL. Mycobacterial stationary phase induced by low oxygen tension: cell wall thickening and localization of the 16-kilodalton α–crystallin homolog. J. Bacteriol. 180(4), 801–808 (1998).
    • 44 Barry CE 3rd, Lee RE, Mdluli K et al. Mycolic acids: structure, biosynthesis and physiological functions. Prog. Lipid Res. 37(2–3), 143–179 (1998).
    • 45 Dubnau E, Chan J, Raynaud C et al. Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Mol. Microbiol. 36(3), 630–637 (2000).
    • 46 Dkhar HK, Nanduri R, Mahajan S et al. Mycobacterium tuberculosis keto-mycolic acid and macrophage nuclear receptor TR4 modulate foamy biogenesis in granulomas: a case of a heterologous and noncanonical ligand-receptor pair. J. Immunol. 193(1), 295–305 (2014).
    • 47 Rao V, Fujiwara N, Porcelli SA et al. Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule. J. Exp. Med. 201(4), 535–543 (2005).
    • 48 Rao V, Gao F, Chen B et al. Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis-induced inflammation and virulence. J. Clin. Invest. 116(6), 1660–1667 (2006).• Shows the role of M. tuberculosis bioactive cell envelope lipids in TB pathogenesis.
    • 49 Glickman MS, Cox JS, Jacobs WR Jr. A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Mol. Cell 5(4), 717–727 (2000).
    • 50 Ojha A, Anand M, Bhatt A et al. GroEL1: a dedicated chaperone involved in mycolic acid biosynthesis during biofilm formation in mycobacteria. Cell 123(5), 861–873 (2005).
    • 51 Vander Beken S, Al Dulayymi JR, Naessens T et al. Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern. Eur. J. Immunol. 41(2), 450–460 (2011).
    • 52 Layre E, Collmann A, Bastian M et al. Mycolic acids constitute a scaffold for mycobacterial lipid antigens stimulating CD1-restricted T cells. Chem. Biol. 16(1), 82–92 (2009).
    • 53 Pan J, Fujiwara N, Oka S et al. Anti-cord factor (trehalose 6,6′dimycolate) IgG antibody in tuberculosis patients recognizes mycolic acid subclasses. Microbiol. Immunol. 43(9), 863–869 (1999).
    • 54 Thanyani ST, Roberts V, Siko DG et al. A novel application of affinity biosensor technology to detect antibodies to mycolic acid in tuberculosis patients. J. Immunol. Methods 332(1–2), 61–72 (2008).
    • 55 Means TK, Wang S, Lien E et al. Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J. Immunol. 163(7), 3920–3927 (1999).
    • 56 Beckman EM, Porcelli SA, Morita CT et al. Recognition of a lipid antigen by CD1-restricted αβ+ T cells. Nature 372(6507), 691–694 (1994).
    • 57 Zhao J, Siddiqui S, Shang S et al. Mycolic acid-specific T cells protect against Mycobacterium tuberculosis infection in a humanized transgenic mouse model. Elife 4, e08525 (2015).
    • 58 Jackson M, Stadthagen G, Gicquel B. Long-chain multiple methyl-branched fatty acid-containing lipids of Mycobacterium tuberculosis: biosynthesis, transport, regulation and biological activities. Tuberculosis (Edinb). 87(2), 78–86 (2007).
    • 59 Besra GS, Bolton RC, McNeil MR et al. Structural elucidation of a novel family of acyltrehaloses from Mycobacterium tuberculosis. Biochemistry 31(40), 9832–9837 (1992).
    • 60 Muñoz M, Lanéelle MA, Luquin M et al. Occurrence of an antigenic triacyl trehalose in clinical isolates and reference strains of Mycobacterium tuberculosis. FEMS Microbiol. Lett. 157(2), 251–259 (1997).
    • 61 Daffé M, Lacave C, Lanéelle MA et al. Polyphthienoyl trehalose, glycolipids specific for virulent strains of the tubercle bacillus. Eur. J. Biochem. 172(3), 579–584 (1988).
    • 62 Goren MB. Mycobacterial fatty acid esters of sugars and sulfosugars. In: Handbook of Lipid Research Glycolipids, Phosphoglycolipids and Sulfoglycolipids. Kates M (Ed.). Springer International, Basel, Switzerland, 363–461 (1990).
    • 63 Nobre A, Alarico S, Maranha A et al. The molecular biology of mycobacterial trehalose in the quest for advanced tuberculosis therapies. Microbiology 160(Pt 8), 1547–1570 (2014).
    • 64 Alibaud L, Pawelczyk J, Gannoun-Zaki L et al. Increased phagocytosis of Mycobacterium marinum mutants defective in lipooligosaccharide production: a structure-activity relationship study. J. Biol. Chem. 289(1), 215–228 (2014).
    • 65 Gonzalo Asensio J, Maia C, Ferrer NL et al. The virulence-associated two-component PhoP–PhoR system controls the biosynthesis of polyketide-derived lipids in Mycobacterium tuberculosis. J. Biol. Chem. 281(3), 1313–1316 (2006).
    • 66 Singh A, Crossman DK, Mai D et al. Mycobacterium tuberculosis WhiB3 maintains redox homeostasis by regulating virulence lipid anabolism to modulate macrophage response. PLoS Pathog. 5(8), e1000545 (2009).
    • 67 Belardinelli JM, Larrouy-Maumus G, Jones V et al. Biosynthesis and translocation of unsulfated acyltrehaloses in Mycobacterium tuberculosis. J. Biol. Chem. 289(40), 27952–27965 (2014).
    • 68 Touchette MH, Holsclaw CM, Previti ML et al. The rv1184c locus encodes Chp2, an acyltransferase in Mycobacterium tuberculosis polyacyltrehalose lipid biosynthesis. J. Bacteriol. 197(1), 201–210 (2015).
    • 69 Husseini H, Elberg S. Cellular reactions to phthienoic acid and related branched-chain acids. Am. Rev. Tuberc. 65(6), 655–672 (1952).
    • 70 Saavedra R, Segura E, Tenorio EP et al. Mycobacterial trehalose-containing glycolipid with immunomodulatory activity on human CD4+ and CD8+ T-cells. Microbes Infect. 8(2), 533–540 (2006).
    • 71 Palma-Nicolás JP, Hernández-Pando R, Segura E et al. Mycobacterial di-O-acyl trehalose inhibits Th-1 cytokine gene expression in murine cells by down-modulation of MAPK signaling. Immunobiology 215(2), 143–152 (2010).
    • 72 Ahmed A, Das A, Mukhopadhyay S. Immunoregulatory functions and expression patterns of PE/PPE family members: roles in pathogenicity and impact on anti-tuberculosis vaccine and drug design. IUBMB Life 67(6), 414–427 (2015).
    • 73 Lee KS, Dubey VS, Kolattukudy PE et al. Diacyltrehalose of Mycobacterium tuberculosis inhibits lipopolysaccharide- and mycobacteria-induced proinflammatory cytokine production in human monocytic cells. FEMS Microbiol. Lett. 267(1), 121–128 (2007).
    • 74 Espinosa-Cueto P, Escalera-Zamudio M, Magallanes-Puebla A et al. Mycobacterial glycolipids di-O-acylated trehalose and tri-O-acylated trehalose downregulate inducible nitric oxide synthase and nitric oxide production in macrophages. BMC Immunol. 16, 38 (2015).
    • 75 Dubey VS, Sirakova TD, Kolattukudy PE. Disruption of msl3 abolishes the synthesis of mycolipanoic and mycolipenic acids required for polyacyltrehalose synthesis in Mycobacterium tuberculosis H37Rv and causes cell aggregation. Mol. Microbiol. 45(5), 1451–1459 (2002).
    • 76 Rousseau C, Neyrolles O, Bordat Y et al. Deficiency in mycolipenate- and mycosanoate-derived acyltrehaloses enhances early interactions of Mycobacterium tuberculosis with host cells. Cell Microbiol. 5(6), 405–415 (2003).
    • 77 Passemar C, Arbués A, Malaga W et al. Multiple deletions in the polyketide synthase gene repertoire of Mycobacterium tuberculosis reveal functional overlap of cell envelope lipids in host-pathogen interactions. Cell Microbiol. 16(2), 195–213 (2014).
    • 78 Goren MB, Brokl O, Das BC. Sulfatides of Mycobacterium tuberculosis: the structure of the principal sulfatide (SL-I). Biochemistry 15(13), 2728–2735 (1976).
    • 79 Asselineau J. Branched-chain fatty acids of mycobacteria. Indian J. Chest Dis. Allied Sci. 24(2–3), 143–157 (1982).
    • 80 Goyal R, Das AK, Singh R et al. Phosphorylation of PhoP protein plays direct regulatory role in lipid biosynthesis of Mycobacterium tuberculosis. J. Biol. Chem. 286(52), 45197–45208 (2011).
    • 81 Middlebrook G, Coleman CM, Schaefer WB. Sulfolipid from virulent tubercle bacilli. Proc. Natl Acad. Sci. USA 45(12), 1801–1804 (1959).
    • 82 Gangadharam PR, Cohn ML, Middlebrook G. Infectivity pathogenicity and sulpholipid fraction of some Indian and British strains of tubercle bacilli. Tubercle 44, 452–455 (1963).
    • 83 Pabst MJ, Gross JM, Brozna JP et al. Inhibition of macrophage priming by sulfatide from Mycobacterium tuberculosis. J. Immunol. 140(2), 634–640 (1988).
    • 84 Brozna JP, Horan M, Rademacher JM et al. Monocyte responses to sulfatide from Mycobacterium tuberculosis: inhibition of priming for enhanced release of superoxide, associated with increased secretion of interleukin-1 and tumor necrosis factor alpha, and altered protein phosphorylation. Infect. Immun. 59(8), 2542–2548 (1991).
    • 85 Zhang L, English D, Andersen BR. Activation of human neutrophils by Mycobacterium tuberculosis-derived sulfolipid-1. J. Immunol. 146(8), 2730–2736 (1991).
    • 86 Zhang L, Goren MB, Holzer TJ et al. Effect of Mycobacterium tuberculosis-derived sulfolipid I on human phagocytic cells. Infect. Immun. 56(11), 2876–2883 (1988).
    • 87 Gilmore SA, Schelle MW, Holsclaw CM et al. Sulfolipid-1 biosynthesis restricts Mycobacterium tuberculosis growth in human macrophages. ACS Chem. Biol. 7(5), 863–870 (2012).
    • 88 Converse SE, Mougous JD, Leavell MD et al. MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. Proc. Natl Acad. Sci. USA 100(10), 6121–6126 (2003).
    • 89 Domenech P, Reed MB, Dowd CS et al. The role of MmpL8 in sulfatide biogenesis and virulence of Mycobacterium tuberculosis. J. Biol. Chem. 279(20), 21257–21265 (2004).
    • 90 Takayama K, Wang C, Besra GS. Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin. Microbiol. Rev. 18(1), 81–101 (2005).
    • 91 Hunter RL, Olsen MR, Jagannath C et al. Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavitary tuberculosis, including a revised description of the pathology of secondary disease. Ann. Clin. Lab. Sci. 36(4), 371–386 (2006).
    • 92 Yamagami H, Matsumoto T, Fujiwara N et al. Trehalose 6,6′-dimycolate (cord factor) of Mycobacterium tuberculosis induces foreign-body- and hypersensitivity-type granulomas in mice. Infect. Immun. 69(2), 810–815 (2001).
    • 93 Harland CW, Botyanszki Z, Rabuka D et al. Synthetic trehalose glycolipids confer desiccation resistance to supported lipid monolayers. Langmuir 25(9), 5193–5198 (2009).
    • 94 Indrigo J, Hunter RL Jr, Actor JK. Cord factor trehalose 6,6′-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages. Microbiology 149(Pt 8), 2049–2059 (2003).
    • 95 Geisel RE, Sakamoto K, Russell DG et al. In vivo activity of released cell wall lipids of Mycobacterium bovis Bacillus Calmette–Guérin is due principally to trehalose mycolates. J. Immunol. 174(8), 5007–5015 (2005).
    • 96 Hamasaki N, Isowa K, Kamada K et al. In vivo administration of mycobacterial cord factor (Trehalose 6,6′-dimycolate) can induce lung and liver granulomas and thymic atrophy in rabbits. Infect. Immun. 68(6), 3704–3709 (2000).
    • 97 Welsh KJ, Hunter RL, Actor JK. Trehalose 6,6′-dimycolate-a coat to regulate tuberculosis immunopathogenesis. Tuberculosis (Edinb). 93(Suppl.), S3–S9 (2013).
    • 98 Ryll R, Watanabe K, Fujiwara N et al. Mycobacterial cord factor, but not sulfolipid, causes depletion of NKT cells and upregulation of CD1d1 on murine macrophages. Microbes Infect. 3(8), 611–619 (2001).
    • 99 Ryll R, Kumazawa Y, Yano I. Immunological properties of trehalose dimycolate (cord factor) and other mycolic acid-containing glycolipids-a review. Microbiol. Immunol. 45(12), 801–811 (2001).
    • 100 Axelrod S, Oschkinat H, Enders J et al. Delay of phagosome maturation by a mycobacterial lipid is reversed by nitric oxide. Cell Microbiol. 10(7), 1530–1545 (2008).
    • 101 Indrigo J, Hunter RL Jr, Actor JK. Influence of trehalose 6,6′-dimycolate (TDM) during mycobacterial infection of bone marrow macrophages. Microbiology 148(Pt 7), 1991–1998 (2002).
    • 102 Kan-Sutton C, Jagannath C, Hunter RL Jr. Trehalose 6, 6′-dimycolate on the surface of Mycobacterium tuberculosis modulates surface marker expression for antigen presentation and co-stimulation in murine macrophages. Microbes Infect. 11(1), 40–48 (2009).
    • 103 Fischer K, Chatterjee D, Torrelles J et al. Mycobacterial lysocardiolipin is exported from phagosomes upon cleavage of cardiolipin by a macrophage-derived lysosomal phospholipase A2. J. Immunol. 167(4), 2187–2192 (2001).
    • 104 Yamasaki S, Ishikawa E, Sakuma M et al. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat. Immunol. 9(10), 1179–1188 (2008).
    • 105 Ishikawa E, Ishikawa T, Morita YS et al. Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J. Exp. Med. 206(13), 2879–2888 (2009).
    • 106 Ramakrishnan L. Revisiting the role of the granuloma in tuberculosis. Nat. Rev. Immunol. 12(5), 352–366 (2012).
    • 107 Kobayashi K, Yoshida T. The immunopathogenesis of granulomatous inflammation induced by Mycobacterium tuberculosis. Methods 9(2), 204–214 (1996).
    • 108 Schoenen H, Bodendorfer B, Hitchens K et al. Cutting edge: Mincle is essential for recognition and adjuvanticity of the mycobacterial cordfactor and its synthetic analog trehalose-dibehenate. J. Immunol. 184(6), 2756–2760 (2010).
    • 109 Riley LW. Of mice, men, and elephants: Mycobacterium tuberculosis cell envelope lipids and pathogenesis. J. Clin. Invest. 116(6), 1475–1478 (2006).
    • 110 Himmler M, Bommineni G, Metz T, Tonge P, Seeliger J. Elucidating biosynthesis of the outer membrane lipid phthiocerol dimycocerosate by Mycobacterium tuberculosis PapA5 (768.13). FASEB J. 28(Suppl. 768), 13 (2014).
    • 111 Murry JP, Pandey AK, Sassetti CM et al. Phthiocerol dimycocerosate transport is required for resisting interferon-gamma-independent immunity. J. Infect. Dis. 200(5), 774–782 (2009).
    • 112 Cambier CJ, Takaki KK, Larson RP et al. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 505(7482), 218–222 (2014).• Demonstrates that M. tuberculosis can evade immune recognition by macrophages upon masking their pattern recognition receptors via cell surface-associated lipids.
    • 113 Cox JS, Chen B, McNeil M et al. Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice. Nature 402(6757), 79–83 (1999).
    • 114 Camacho LR, Constant P, Raynaud C et al. Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis. Evidence that this lipid is involved in the cell wall permeability barrier. J. Biol. Chem. 276(23), 19845–19854 (2001).
    • 115 Quigley J, Hughitt VK, Velikovsky CA et al. The cell wall lipid PDIM contributes to phagosomal escape and host cell exit of Mycobacterium tuberculosis. MBio 8(2), e00148–e00217 (2017).
    • 116 Purwantini E, Daniels L, Mukhopadhyay B. F420H2 is required for phthiocerol dimycocerosate synthesis in mycobacteria. J. Bacteriol. 198(15), 2020–2028 (2016).
    • 117 Boonyarattanakalin S, Liu X, Michieletti M et al. Chemical synthesis of all phosphatidylinositol mannoside (PIM) glycans from Mycobacterium tuberculosis. J. Am. Chem. Soc. 130(49), 16791–16799 (2008).
    • 118 Guerin ME, Korduláková J, Alzari PM et al. Molecular basis of phosphatidyl-myo-inositol mannoside biosynthesis and regulation in mycobacteria. J. Biol. Chem. 285(44), 33577–33583 (2010).
    • 119 Bansal-Mutalik R, Nikaido H. Mycobacterial outer membrane is a lipid bilayer and the inner membrane is unusually rich in diacyl phosphatidylinositol dimannosides. Proc. Natl Acad. Sci. USA 111(13), 4958–4963 (2014).
    • 120 Court N, Rose S, Bourigault ML et al. Mycobacterial PIMs inhibit host inflammatory responses through CD14-dependent and CD14-independent mechanisms. PLoS ONE 6(9), e24631 (2011).
    • 121 Apostolou I, Takahama Y, Belmant C et al. Murine natural killer cells contribute to the granulomatous reaction caused by mycobacterial cell walls. Proc. Natl Acad. Sci. USA 96(9), 5141–5146 (1999).
    • 122 Toyonaga K, Torigoe S, Motomura Y et al. C-Type lectin receptor DCAR recognizes mycobacterial phosphatidyl-inositol mannosides to promote a Th1 response during Infection. Immunity 45(6), 1245–1257 (2016).
    • 123 Rojas RE, Thomas JJ, Gehring AJ et al. Phosphatidylinositol mannoside from Mycobacterium tuberculosis binds α5β1 integrin (VLA-5) on CD4+ T cells and induces adhesion to fibronectin. J. Immunol. 177(5), 2959–2968 (2006).
    • 124 Nigou J, Gilleron M, Puzo G. Lipoarabinomannans: from structure to biosynthesis. Biochimie 85(1–2), 153–166 (2003).
    • 125 Quesniaux VJ, Nicolle DM, Torres D et al. Toll-like receptor 2 (TLR2)-dependent-positive and TLR2-independent-negative regulation of proinflammatory cytokines by mycobacterial lipomannans. J. Immunol. 172(7), 4425–4434 (2004).
    • 126 Rajaram MV, Ni B, Morris JD et al. Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b. Proc. Natl Acad. Sci. USA 108(42), 17408–17413 (2011).
    • 127 Hunter SW, Brennan PJ. Evidence for the presence of a phosphatidylinositol anchor on the lipoarabinomannan and lipomannan of Mycobacterium tuberculosis. J. Biol. Chem. 265(16), 9272–9279 (1990).
    • 128 Rastogi N. Recent observations concerning structure and function relationships in the mycobacterial cell envelope: elaboration of a model in terms of mycobacterial pathogenicity, virulence and drug-resistance. Res. Microbiol. 142(4), 464–476 (1991).
    • 129 Alsteens D, Verbelen C, Dague E et al. Organization of the mycobacterial cell wall: a nanoscale view. Pflugers Arch. 456(1), 117–125 (2008).
    • 130 Strohmeier GR, Fenton MJ. Roles of lipoarabinomannan in the pathogenesis of tuberculosis. Microbes Infect. 1(9), 709–717 (1999).
    • 131 Nigou J, Gilleron M, Rojas M et al. Mycobacterial lipoarabinomannans: modulators of dendritic cell function and the apoptotic response. Microbes Infect. 4(9), 945–953 (2002).
    • 132 Underhill DM, Ozinsky A, Smith KD et al. Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages. Proc. Natl Acad. Sci. USA 96(25), 14459–14463 (1999).
    • 133 Puissegur MP, Lay G, Gilleron M et al. Mycobacterial lipomannan induces granuloma macrophage fusion via a TLR2-dependent, ADAM9- and β1 integrin-mediated pathway. J. Immunol. 178(5), 3161–3169 (2007).
    • 134 Fratti RA, Backer JM, Gruenberg J et al. Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J. Cell Biol. 154(3), 631–644 (2001).
    • 135 Vergne I, Chua J, Deretic V. Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2+/calmodulin-PI3K hVPS34 cascade. J. Exp. Med. 198(4), 653–659 (2003).
    • 136 Sande OJ, Karim AF, Li Q et al. Mannose-capped lipoarabinomannan from Mycobacterium tuberculosis induces CD4+ T cell anergy via GRAIL. J. Immunol. 196(2), 691–702 (2016).
    • 137 Nakayama H, Kurihara H, Morita YS et al. Lipoarabinomannan binding to lactosylceramide in lipid rafts is essential for the phagocytosis of mycobacteria by human neutrophils. Sci. Signal. 9(449), ra101 (2016).
    • 138 Yonekawa A, Saijo S, Hoshino Y et al. Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of mycobacteria. Immunity 41, 402–413 (2014).
    • 139 Pan Q, Yan J, Liu Q et al. A single-stranded DNA aptamer against mannose-capped lipoarabinomannan enhances anti-tuberculosis activity of macrophages through downregulation of lipid-sensing nuclear receptor peroxisome proliferator-activated receptor γ expression. Microbiol. Immunol. 61(2), 92–102 (2017).
    • 140 Khoo KH, Dell A, Morris HR et al. Inositol phosphate capping of the non-reducing termini of lipoarabinomannan from rapidly growing strains of Mycobacterium. J. Biol. Chem. 270(21), 12380–12389 (1995).
    • 141 Guerardel Y, Maes E, Elass E et al. Structural study of lipomannan and lipoarabinomannan from Mycobacterium chelonae. Presence of unusual components with alpha 1,3-mannopyranose side chains. J. Biol. Chem. 277(34), 30635–30648 (2002).
    • 142 Dhiman RK, Dinadayala P, Ryan GJ et al. Lipoarabinomannan localization and abundance during growth of Mycobacterium smegmatis. J. Bacteriol. 193(20), 5802–5809 (2011).
    • 143 Kang PB, Azad AK, Torrelles JB et al. The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis. J. Exp. Med. 202(7), 987–999 (2005).
    • 144 Rojas M, García LF, Nigou J, Puzo G, Olivier M. Mannosylated lipoarabinomannan antagonizes Mycobacterium tuberculosis-induced macrophage apoptosis by altering Ca+2-dependent cell signaling. J. Infect. Dis. 182(1), 240–251 (2000).
    • 145 Astarie-Dequeker C, Nigou J, Puzo G, Maridonneau-Parini I. Lipoarabinomannans activate the protein tyrosine kinase Hck in human neutrophils. Infect. Immun. 68(8), 4827–4830 (2000).
    • 146 Dao DN, Kremer L, Guérardel Y et al. Mycobacterium tuberculosis lipomannan induces apoptosis and interleukin-12 production in macrophages. Infect. Immun. 72(4), 2067–2074 (2004).
    • 147 Fratti RA, Chua J, Vergne I, Deretic V. Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Proc. Natl Acad. Sci. USA 100(9), 5437–5442 (2003).
    • 148 Appelmelk BJ, den Dunnen J, Driessen NN et al. The mannose cap of mycobacterial lipoarabinomannan does not dominate the Mycobacterium–host interaction. Cell Microbiol. 10(4), 930–944 (2008).
    • 149 Daffé M, Laneelle MA. Distribution of phthiocerol diester, phenolic mycosides and related compounds in mycobacteria. J. Gen. Microbiol. 134(7), 2049–2055 (1988).
    • 150 Constant P, Perez E, Malaga W et al. Role of the pks15/1 gene in the biosynthesis of phenolglycolipids in the Mycobacterium tuberculosis complex. Evidence that all strains synthesize glycosylated p-hydroxybenzoic methyl esters and that strains devoid of phenolglycolipids harbor a frameshift mutation in the pks15/1 gene. J. Biol. Chem. 277(41), 38148–38158 (2002).
    • 151 Ortalo-Magné A, Lemassu A, Lanéelle MA et al. Identification of the surface-exposed lipids on the cell envelopes of Mycobacterium tuberculosis and other mycobacterial species. J. Bacteriol. 178(2), 456–461 (1996).
    • 152 Minnikin DE. Lipids: complex lipids, their chemistry, biosynthesis and roles. In: The Biology of Mycobacteria. Ratledge C, Stanford J (Eds). Academic Press, London, United Kingdom, 95–184 (1982).
    • 153 Onwueme KC, Vos CJ, Zurita J et al. The dimycocerosate ester polyketide virulence factors of mycobacteria. Prog. Lipid Res. 44(5), 259–302 (2005).
    • 154 Hartmann S, Minnikin DE. Mycobacterial phenolic glycolipids. In: Surfactants in Lipid Chemistry. Tyman JHP (Ed.). Royal Society of Chemistry, Cambridge, United Kingdom, 135–158 (1992).
    • 155 Betts JC, Lukey PT, Robb LC et al. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol. Microbiol. 43(3), 717–731 (2002).
    • 156 Reed MB, Domenech P, Manca C et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431(7004), 84–87 (2004).
    • 157 Tran V, Ahn SK, Ng M et al. Loss of lipid virulence factors reduces the efficacy of the BCG vaccine. Sci. Rep. 6, 29076 (2016).
    • 158 Sinsimer D, Huet G, Manca C et al. The phenolic glycolipid of Mycobacterium tuberculosis differentially modulates the early host cytokine response but does not in itself confer hypervirulence. Infect. Immun. 76(7), 3027–3036 (2008).
    • 159 Fäldt J, Dahlgren C, Karlsson A, Ahmed AM, Minnikin DE, Ridell M. Activation of human neutrophils by mycobacterial phenolic glycolipids. Clin. Exp. Immunol. 118(2), 253–260 (1999).
    • 160 Robinson N, Kolter T, Wolke M, Rybniker J, Hartmann P, Plum G. Mycobacterial phenolic glycolipid inhibits phagosome maturation and subverts the pro-inflammatory cytokine response. Traffic 9(11), 1936–1947 (2008).
    • 161 Spencer JS, Brennan PJ. The role of Mycobacterium leprae phenolic glycolipid I (PGL-I) in serodiagnosis and in the pathogenesis of leprosy. Lepr. Rev. 82(4), 344–357 (2011).
    • 162 Arbués A, Malaga W, Constant P, Guilhot C, Prandi J, Astarie-Dequeker C. Trisaccharides of phenolic glycolipids confer advantages to pathogenic mycobacteria through manipulation of host-cell pattern-recognition receptors. ACS Chem. Biol. 11(10), 2865–2875 (2016).
    • 163 Banerjee A, Dubnau E, Quemard A et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263, 227–230 (1994).
    • 164 Larsen MH, Vilcheze C, Kremer L et al. Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis. Mol. Microbiol. 46, 453–466 (2002).
    • 165 Marrakchi H, Lanéelle G, Quémard A. InhA, a target of the anti-tuberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II. Microbiology 146(Pt 2), 289–296 (2000).
    • 166 Stehr M, Elamin AA, Singh M. Filling the pipeline – new drugs for an old disease. Curr. Top. Med. Chem. 14(1), 110–129 (2014).
    • 167 Bogatcheva E, Hanrahan C, Nikonenko B et al. Identification of new diamine scaffolds with activity against Mycobacterium tuberculosis. J. Med. Chem. 49, 3045–3048 (2006).
    • 168 Li K, Schurig-Briccio LA, Feng X et al. Multitarget drug discovery for tuberculosis and other infectious diseases. J. Med. Chem. 57(7), 3126–3139 (2014).
    • 169 Sacksteder KA, Protopopova M, Barry CE 3rd, Andries K, Nacy CA. Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action. Future Microbiol. 7(7), 823–837 (2012).
    • 170 Bruning JB, Murillo AC, Chacon O et al. Structure of the Mycobacterium tuberculosis D-alanine:D-alanine ligase, a target of the antituberculosis drug D-cycloserine. Antimicrob. Agents Chemother. 55, 291–301 (2011).
    • 171 Prosser GA, de Carvalho LP. Kinetic mechanism and inhibition of Mycobacterium tuberculosis D-alanine:D-alanine ligase by the antibiotic D-cycloserine. FEBS J. 280, 1150–1166 (2013).
    • 172 Kurosu M, Mahapatra S, Narayanasamy P et al. Chemoenzymatic synthesis of Park's nucleotide: toward the development of high-throughput screening for MraY inhibitors. Tetrahedron Lett. 48, 799–803 (2007).
    • 173 Dini C. MraY inhibitors as novel antibacterial agents. Curr. Top. Med. Chem. 5, 1221–1236 (2005).
    • 174 Reynolds PE. Structure biochemistry and mechanism of action of glycopeptide antibiotics. Eur. J. Clin. Microbiol. Infect. Dis. 8, 943–950 (1989).
    • 175 Wiedemann I, Breukink E, van Kraaij C et al. Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity. J. Biol. Chem. 276(3), 1772–1779 (2001).
    • 176 Lo MC, Men H, Branstrom A et al. A new mechanism of action proposed for ramoplanin. J. Am. Chem. Soc. 122, 3540–3541 (2000).
    • 177 Christophe T, Jackson M, Jeon HK et al. High content screening identifies decaprenyl-phosphoribose 2′ epimerase as a target for intracellular antimycobacterial inhibitors. PLoS Pathog. 5(10), e1000645 (2009).
    • 178 Batt SM, Jabeen T, Bhowruth V et al. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proc. Natl Acad. Sci. USA 109(28), 11354–11359 (2012).
    • 179 Makarov V, Lechartier B, Zhang M et al. Towards a new combination therapy for tuberculosis with next generation benzothiazinones. EMBO Mol. Med. 6(3), 372–383 (2014).
    • 180 Makarov V, Neres J, Hartkoorn RC et al. The 8-pyrrole-benzothiazinones are noncovalent inhibitors of DprE1 from Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 59(8), 4446–4452 (2015).
    • 181 Gurcha SS, Baulard AR, Kremer L et al. Ppm1, a novel polyprenol monophosphomannose synthase from Mycobacterium tuberculosis. Biochem. J. 365(Pt 2), 441–450 (2002).
    • 182 Banerjee DK, Scher MG, Waechter CJ. Amphomycin: effect of the lipopeptide antibiotic on the glycosylation and extraction of dolichyl monophosphate in calf brain membranes. Biochemistry 20, 1561–1568 (1981).
    • 183 Gavalda S, Léger M, van der Rest B et al. The Pks13/FadD32 crosstalk for the biosynthesis of mycolic acids in Mycobacterium tuberculosis. J. Biol. Chem. 284(29), 19255–19264 (2009).
    • 184 Portevin D, De Sousa-D'Auria C, Houssin C et al. A polyketide synthase catalyzes the last condensation step of mycolic acid biosynthesis in mycobacteria and related organisms. Proc. Natl Acad. Sci. USA 101(1), 314–319 (2004).
    • 185 Wilson R, Kumar P, Parashar V et al. Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nat. Chem. Biol. 9(8), 499–506 (2013).
    • 186 Stanley SA, Kawate T, Iwase N et al. Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32. Proc. Natl Acad. Sci. USA 110(28), 11565–11570 (2013).
    • 187 Bailo R, Bhatt A, Aínsa JA. Lipid transport in Mycobacterium tuberculosis and its implications in virulence and drug development. Biochem. Pharmacol. 96(3), 159–167 (2015).
    • 188 La Rosa V, Poce G, Canseco JO et al. MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212. Antimicrob. Agents Chemother. 56(1), 324–331 (2012).
    • 189 Grzegorzewicz AE, Pham H, Gundi VA et al. Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat. Chem. Biol. 8(4), 334–341 (2012).•• Identified an adamantyl urea compound that shows potent bactericidal activity against M. tuberculosis by obliteration of the translocation of mycolic acids from the cytoplasm to the plasma membrane.
    • 190 Stanley SA, Grant SS, Kawate T et al. Identification of novel inhibitors of M. tuberculosis growth using whole cell based high-throughput screening. ACS Chem. Biol. 7(8), 1377–1384 (2012).
    • 191 Li W, Sanchez-Hidalgo A, Jones V et al. Synergistic interactions of MmpL3 inhibitors with antitubercular compounds in vitro. Antimicrob. Agents Chemother. 61(4), e02399–e02416 (2017).
    • 192 Belardinelli JM, Yazidi A, Yang L et al. Structure–function profile of MmpL3, the essential mycolic acid transporter from Mycobacterium tuberculosis. ACS Infect. Dis. 2(10), 702–713 (2016).
    • 193 Elamin AA, Stehr M, Oehlmann W et al. The mycolyltransferase 85A, a putative drug target of Mycobacterium tuberculosis: development of a novel assay and quantification of glycolipid-status of the mycobacterial cell wall. J. Microbiol. Methods 79(3), 358–363 (2009).
    • 194 Warrier T, Tropis M, Werngren J et al. Antigen 85C inhibition restricts Mycobacterium tuberculosis growth through disruption of cord factor biosynthesis. Antimicrob. Agents Chemother. 56(4), 1735–1743 (2012).
    • 195 Favrot L, Ronning DR. Targeting the mycobacterial envelope for tuberculosis drug development. Expert Rev. Anti. Infect. Ther. 10(9), 1023–1036 (2012).
    • 196 Ryndak M, Wang S, Smith I. PhoP a key player in Mycobacterium tuberculosis virulence. Trends Microbiol. 16(11), 528–534 (2008).
    • 197 North EJ, Jackson M, Lee RE. New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics. Curr. Pharm. Des. 20(27), 4357–4378 (2014).
    • 198 Zhang Q, Liu Y, Tang S, Sha W, Xiao H. Clinical benefit of delamanid (OPC-67683) in the treatment of multidrug-resistant tuberculosis patients in China. Cell Biochem. Biophys. 67(3), 957–963 (2013).
    • 199 Stover CK, Warrener P, VanDevanter DR et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405(6789), 962–966 (2000).
    • 200 Mdluli K, Kaneko T, Upton A. The tuberculosis drug discovery and development pipeline and emerging drug targets. Cold Spring Harb. Perspect. Med. 5(6), a021154 (2015).
    • 201 Dawson R, Diacon AH, Everitt D et al. Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis. Lancet 385(9979), 1738–1747 (2015).•• First report which shows that the combination of moxifloxacin, pretomanid (formerly known as PA-824) and pyrazinamide (MPaZ regimen) has been used for multidrug-resistant TB.
    • 202 Reyes F, Tirado Y, Puig A et al. Immunogenicity and cross-reactivity against Mycobacterium tuberculosis of proteoliposomes derived from Mycobacterium bovis BCG. BMC Immunol. 14, S7 (2013).
    • 203 Gilleron M, Stenger S, Mazorra Z et al. Diacylated sulfoglycolipids are novel mycobacterial antigens stimulating CD1-restricted T cells during infection with Mycobacterium tuberculosis. J. Exp. Med. 199, 649–659 (2004).
    • 204 Moody DB, Ulrichs T, Muhlecker W et al. CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature 404, 884–888 (2000).
    • 205 Sieling PA, Chatterjee D, Porcelli SA et al. CD1-restricted T cell recognition of microbial lipoglycan antigens. Science 269, 227–230 (1995).
    • 206 Moody DB, Reinhold BB, Guy MR et al. Structural requirements for glycolipid antigen recognition by CD1b-restricted T cells. Science 278, 283–286 (1997).
    • 207 Gumperz JE, Roy C, Makowska A et al. Murine CD1d-restricted T cell recognition of cellular lipids. Immunity 12, 211–221 (2000).
    • 208 Kawano T, Cui J, Koezuka Y et al. CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).
    • 209 Moody DB, Guy MR, Grant E et al. CD1b-mediated T cell recognition of a glycolipid antigen generated from mycobacterial lipid and host carbohydrate during infection. J. Exp. Med. 192(7), 965–976 (2000).
    • 210 Montamat-Sicotte DJ, Millington KA, Willcox CR et al. A mycolic acid-specific CD1-restricted T cell population contributes to acute and memory immune responses in human tuberculosis infection. J. Clin. Investig. 121, 2493–2503 (2011).
    • 211 Lenaerts AJ, Hoff D, Aly S et al. Location of persisting mycobacteria in a Guinea pig model of tuberculosis revealed by r207910. Antimicrob. Agents Chemother. 51(9), 3338–3345 (2007).
    • 212 Larrouy-Maumus G, Layre E, Clark S et al. Protective efficacy of a lipid antigen vaccine in a guinea pig model of tuberculosis. Vaccine 35(10), 1395–1402 (2017).
    • 213 Lechartier B, Hartkoorn RC, Cole ST. In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 56(11), 5790–5793 (2012).
    • 214 Means TK, Wang S, Lien E et al. Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J. Immunol. 163(7), 3920–3927 (1999).