Advertisement

Mycolic Acids: From Chemistry to Biology

  • Mamadou DafféEmail author
  • Annaïk Quémard
  • Hedia Marrakchi
Reference work entry
Part of the Handbook of Hydrocarbon and Lipid Microbiology book series (HHLM)

Abstract

Mycolic acids are exceptionally long-chain fatty acids that are major and specific lipid components of the cell envelope of members of the Corynebacteriales order, which includes the causative agents of both tuberculosis and leprosy. These acids participate to the composition of the recently discovered “outer membrane,” a component unexpected for these Gram-positive microorganisms. Many proteins involved in mycolic acid biosynthesis and transport are essential for the mycobacterial survival and represent both validated targets and highly relevant candidates for the development of novel antimycobacterial agents, in the alarming context of multidrug-resistant tuberculosis.

Notes

Acknowledgments

The authors are grateful to their colleagues for fruitful collaborations and discussions, and for sharing unpublished material. We acknowledge funding from the European Union (NM4TB, grant LSHP-CT-2005-018923; TB-Drug grant LSHP-CT-2006-037217; SysteMTb HEALTH-2009-2.1.2-1 241587), the Agence Nationale de la Recherche (XPKS-MYCO, grant 09-BLAN-0298-03; FASMY, grant ANR-14-CE16-0012), the Région Midi-Pyrénées (MYCA, FEDER grant 34249), the France-Argentina ECOS-MINCyT cooperation program (grant A11B04) and the “Vaincre la Mucoviscidose” association (IC0716, France).

References

  1. Alahari A, Trivelli X, Guerardel Y, Dover LG, Besra GS, Sacchettini JC, Reynolds RC, Coxon GD, Kremer L (2007) Thiacetazone, an antitubercular drug that inhibits cyclopropanation of cell wall mycolic acids in mycobacteria. PLoS One 2:e1343PubMedPubMedCentralCrossRefGoogle Scholar
  2. Asselineau C, Asselineau J (1966) Stéréochimie de l’acide corynomycolique. Bull Soc Chim Fr 6:1992–1999Google Scholar
  3. Asselineau J, Lederer E (1950) Structure of the mycolic acids of mycobacteria. Nature 166:782–783PubMedCrossRefPubMedCentralGoogle Scholar
  4. Asselineau C, Tocanne G, Tocanne JF (1970a) Stéréochimie des acides mycoliques. Bull Soc Chim Fr 4:1455–1459Google Scholar
  5. Asselineau CP, Lacave CS, Montrozier HL, Prome JC (1970b) Structural relations between unsaturated mycolic acids and short-chain unsaturated acids synthesized by Mycobacterium phlei. Metabolic implications. Eur J Biochem 14:406–410PubMedCrossRefPubMedCentralGoogle Scholar
  6. Asselineau C, Asselineau J, Laneelle G, Laneelle MA (2002) The biosynthesis of mycolic acids by mycobacteria: current and alternative hypotheses. Prog Lipid Res 41:501–523PubMedCrossRefPubMedCentralGoogle Scholar
  7. Av-Gay Y, Everett M (2000) The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis. Trends Microbiol 8:238–244PubMedCrossRefPubMedCentralGoogle Scholar
  8. Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, Collins D, de Lisle G, Jacobs WR Jr (1994) inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263:227–230CrossRefGoogle Scholar
  9. Bardou F, Quemard A, Dupont MA, Horn C, Marchal G, Daffe M (1996) Effects of isoniazid on ultrastructure of Mycobacterium aurum and Mycobacterium tuberculosis and on production of secreted proteins. Antimicrob Agents Chemother 40:2459–2467PubMedPubMedCentralCrossRefGoogle Scholar
  10. Basso LA, Zheng R, Musser JM, Jacobs WR Jr, Blanchard JS (1998) Mechanisms of isoniazid resistance in Mycobacterium tuberculosis: enzymatic characterization of enoyl reductase mutants identified in isoniazid-resistant clinical isolates. J Infect Dis 178:769–775PubMedCrossRefPubMedCentralGoogle Scholar
  11. Bazet Lyonnet B, Diacovich L, Cabruja M, Bardou F, Quemard A, Gago G, Gramajo H (2014) Pleiotropic effect of AccD5 and AccE5 depletion in acyl-coenzyme A carboxylase activity and in lipid biosynthesis in mycobacteria. PLoS One 6:e99853CrossRefGoogle Scholar
  12. Belardinelli JM, Morbidoni HR (2012) Mutations in the essential FAS II beta-hydroxyacyl ACP dehydratase complex confer resistance to thiacetazone in Mycobacterium tuberculosis and Mycobacterium kansasii. Mol Microbiol 86:568–579PubMedCrossRefPubMedCentralGoogle Scholar
  13. Belisle JT, Vissa VD, Sievert T, Takayama K, Brennan PJ, Besra GS (1997) Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis. Science 276:1420–1422PubMedCrossRefPubMedCentralGoogle Scholar
  14. Bergeret F, Gavalda S, Chalut C, Malaga W, Quemard A, Pedelacq JD, Daffe M, Guilhot C, Mourey L, Bon C (2012) Biochemical and structural study of the atypical acyltransferase domain from the mycobacterial polyketide synthase Pks13. J Biol Chem 287:33675–33690PubMedPubMedCentralCrossRefGoogle Scholar
  15. Bhatt A, Kremer L, Dai AZ, Sacchettini JC, Jacobs WR Jr (2005) Conditional depletion of KasA, a key enzyme of mycolic acid biosynthesis, leads to mycobacterial cell lysis. J Bacteriol 187:7596–7606PubMedPubMedCentralCrossRefGoogle Scholar
  16. Bhatt A, Molle V, Besra GS, Jacobs WR Jr, Kremer L (2007a) The Mycobacterium tuberculosis FAS-II condensing enzymes: their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development. Mol Microbiol 64:1442–1454PubMedCrossRefPubMedCentralGoogle Scholar
  17. Bhatt A, Fujiwara N, Bhatt K, Gurcha SS, Kremer L, Chen B, Chan J, Porcelli SA, Kobayashi K, Besra GS, Jacobs WR Jr (2007b) Deletion of kasB in Mycobacterium tuberculosis causes loss of acid-fastness and subclinical latent tuberculosis in immunocompetent mice. Proc Natl Acad Sci U S A 104:5157–5162PubMedPubMedCentralCrossRefGoogle Scholar
  18. Bhatt A, Brown AK, Singh A, Minnikin DE, Besra GS (2008) Loss of a mycobacterial gene encoding a reductase leads to an altered cell wall containing beta-oxo-mycolic acid analogs and accumulation of ketones. Chem Biol 15:930–939PubMedPubMedCentralCrossRefGoogle Scholar
  19. Biswas RK, Dutta D, Tripathi A, Feng Y, Banerjee M, Singh BN (2013) Identification and characterization of Rv0494: a fatty acid-responsive protein of the GntR/FadR family from Mycobacterium tuberculosis. Microbiology 159:913–923PubMedCrossRefPubMedCentralGoogle Scholar
  20. Bloch K (1969) Enzymatic synthesis of monounsaturated fatty acids. Acc Chem Res 2:193–202CrossRefGoogle Scholar
  21. Bloch K (1977) Control mechanisms for fatty acid synthesis in Mycobacterium smegmatis. Adv Enzymol Relat Areas Mol Biol 45:1–84PubMedPubMedCentralGoogle Scholar
  22. Bloch K, Vance D (1977) Control mechanisms in the synthesis of saturated fatty acids. Annu Rev Biochem 46:263–298PubMedCrossRefPubMedCentralGoogle Scholar
  23. Boehringer D, Ban N, Leibundgut M (2013) 7.5-A cryo-em structure of the mycobacterial fatty acid synthase. J Mol Biol 425:841–849PubMedCrossRefPubMedCentralGoogle Scholar
  24. Bordet C, Michel G (1969) Structure and biogenesis of high molecular weight lipids from Nocardia asteroides. Bull Soc Chim Biol (Paris) 51:527–548Google Scholar
  25. Brown JR, North EJ, Hurdle JG, Morisseau C, Scarborough JS, Sun D, Kordulakova J, Scherman MS, Jones V, Grzegorzewicz A, Crew RM, Jackson M, McNeil MR, Lee RE (2011) The structure-activity relationship of urea derivatives as anti-tuberculosis agents. Bioorg Med Chem 19:5585–5595PubMedPubMedCentralCrossRefGoogle Scholar
  26. Cantaloube S, Veyron-Churlet R, Haddache N, Daffe M, Zerbib D (2011) The Mycobacterium tuberculosis FAS-II dehydratases and methyltransferases define the specificity of the mycolic acid elongation complexes. PLoS One 6:e29564PubMedPubMedCentralCrossRefGoogle Scholar
  27. Cantrell SA, Leavell MD, Marjanovic O, Iavarone AT, Leary JA, Riley LW (2013) Free mycolic acid accumulation in the cell wall of the mce1 operon mutant strain of Mycobacterium tuberculosis. J Microbiol 51:619–626PubMedCrossRefPubMedCentralGoogle Scholar
  28. Carel C, Nukdee K, Cantaloube S, Bonne M, Diagne CT, Laval F, Daffe M, Zerbib D (2014) Mycobacterium tuberculosis proteins involved in mycolic acid synthesis and transport localize dynamically to the old growing pole and septum. PLoS One 9:e97148PubMedPubMedCentralCrossRefGoogle Scholar
  29. Carrere-Kremer S, Blaise M, Singh VK, Alibaud L, Tuaillon E, Halloum I, van de Weerd R, Guerardel Y, Drancourt M, Takiff H, Geurtsen J, Kremer L (2015) A new dehydratase conferring innate resistance to thiacetazone and intra-amoebal survival of Mycobacterium smegmatis. Mol Microbiol 96:1085–1102PubMedCrossRefPubMedCentralGoogle Scholar
  30. Carroll P, Faray-Kele MC, Parish T (2011) Identifying vulnerable pathways in Mycobacterium tuberculosis by using a knockdown approach. Appl Environ Microbiol 77:5040–5043PubMedPubMedCentralCrossRefGoogle Scholar
  31. Ciccarelli L, Connell SR, Enderle M, Mills DJ, Vonck J, Grininger M (2013) Structure and conformational variability of the Mycobacterium tuberculosis fatty acid synthase multienzyme complex. Structure 21:1251–1257PubMedCrossRefPubMedCentralGoogle Scholar
  32. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Barrell BG (1998) Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544PubMedCrossRefPubMedCentralGoogle Scholar
  33. Corrales RM, Molle V, Leiba J, Mourey L, de Chastellier C, Kremer L (2012) Phosphorylation of mycobacterial PcaA inhibits mycolic acid cyclopropanation: consequences for intracellular survival and for phagosome maturation block. J Biol Chem 287:26187–26199PubMedPubMedCentralCrossRefGoogle Scholar
  34. Daffé M, Draper P (1998) The envelope layers of mycobacteria with reference to their pathogenicity. Adv Microb Physiol 39:131–203PubMedCrossRefPubMedCentralGoogle Scholar
  35. Daffé M, Laneelle MA, Asselineau C, Levy-Frebault V, David H (1983) Taxonomic value of mycobacterial fatty acids: proposal for a method of analysis. Ann Microbiol (Paris) 134B:241–256Google Scholar
  36. De Sousa-D’Auria C, Kacem R, Puech V, Tropis M, Leblon G, Houssin C, Daffe M (2003) New insights into the biogenesis of the cell envelope of corynebacteria: identification and functional characterization of five new mycoloyltransferase genes in Corynebacterium glutamicum. FEMS Microbiol Lett 224:35–44PubMedCrossRefPubMedCentralGoogle Scholar
  37. DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE 3rd (2000) Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 97:9677–9682PubMedPubMedCentralCrossRefGoogle Scholar
  38. Dessen A, Quemard A, Blanchard JS, Jacobs WR Jr, Sacchettini JC (1995) Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Science 267:1638–1641PubMedCrossRefPubMedCentralGoogle Scholar
  39. Dinadayala P, Laval F, Raynaud C, Lemassu A, Laneelle MA, Laneelle G, Daffe M (2003) Tracking the putative biosynthetic precursors of oxygenated mycolates of Mycobacterium tuberculosis. Structural analysis of fatty acids of a mutant strain deviod of methoxy- and ketomycolates. J Biol Chem 278:7310–7319PubMedCrossRefPubMedCentralGoogle Scholar
  40. Douglas JD, Senior SJ, Morehouse C, Phetsukiri B, Campbell IB, Besra GS, Minnikin DE (2002) Analogues of thiolactomycin: potential drugs with enhanced anti-mycobacterial activity. Microbiology 148:3101–3109PubMedCrossRefPubMedCentralGoogle Scholar
  41. Dover LG, Alahari A, Gratraud P, Gomes JM, Bhowruth V, Reynolds RC, Besra GS, Kremer L (2007) EthA, a common activator of thiocarbamide-containing drugs acting on different mycobacterial targets. Antimicrob Agents Chemother 51:1055–1063PubMedPubMedCentralCrossRefGoogle Scholar
  42. Draper P (1998) The outer parts of the mycobacterial envelope as permeability barriers. Front Biosci 3:D1253–D1261PubMedCrossRefPubMedCentralGoogle Scholar
  43. Dubnau E, Laneelle MA, Soares S, Benichou A, Vaz T, Prome D, Prome JC, Daffe M, Quemard A (1997) Mycobacterium bovis BCG genes involved in the biosynthesis of cyclopropyl keto- and hydroxy-mycolic acids. Mol Microbiol 23:313–322PubMedCrossRefPubMedCentralGoogle Scholar
  44. Dubnau E, Marrakchi H, Smith I, Daffe M, Quemard A (1998) Mutations in the cmaB gene are responsible for the absence of methoxymycolic acid in Mycobacterium bovis BCG Pasteur. Mol Microbiol 29:1526–1528PubMedPubMedCentralGoogle Scholar
  45. Dubnau E, Chan J, Raynaud C, Mohan VP, Laneelle MA, Yu K, Quemard A, Smith I, Daffe M (2000) Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Mol Microbiol 36:630–637PubMedCrossRefPubMedCentralGoogle Scholar
  46. Dupont C, Viljoen A, Dubar F, Blaise M, Bernut A, Pawlik A, Bouchier C, Brosch R, Guerardel Y, Lelievre J, Ballell L, Herrmann JL, Biot C, Kremer L (2016) A new piperidinol derivative targeting mycolic acid transport in Mycobacterium abscessus. Mol Microbiol 101:515–529PubMedCrossRefPubMedCentralGoogle Scholar
  47. Etemadi AH (1967) Structural and biogenetic correlations of mycolic acids in relation to the phylogenesis of various genera of Actinomycetales. Bull Soc Chim Biol (Paris) 49:695–706Google Scholar
  48. Etemadi AH, Gasche J (1965) On the biogenetic origin of 2-eicosanol and 2-octadecanol of Mycobacterium avium. Bull Soc Chim Biol (Paris) 47:2095–2104Google Scholar
  49. Ferrer NL, Gomez AB, Soto CY, Neyrolles O, Gicquel B, Garcia-Del Portillo F, Martin C (2009) Intracellular replication of attenuated Mycobacterium tuberculosis phoP mutant in the absence of host cell cytotoxicity. Microbes Infect 11:115–122PubMedCrossRefPubMedCentralGoogle Scholar
  50. Flipo M, Willand N, Lecat-Guillet N, Hounsou C, Desroses M, Leroux F, Lens Z, Villeret V, Wohlkonig A, Wintjens R, Christophe T, Kyoung Jeon H, Locht C, Brodin P, Baulard AR, Deprez B (2012) Discovery of novel N-phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis. J Med Chem 55:6391–6402PubMedCrossRefPubMedCentralGoogle Scholar
  51. Forrellad MA, McNeil M, Santangelo Mde L, Blanco FC, Garcia E, Klepp LI, Huff J, Niederweis M, Jackson M, Bigi F (2014) Role of the Mce1 transporter in the lipid homeostasis of Mycobacterium tuberculosis. Tuberculosis (Edinb) 94:170–177CrossRefGoogle Scholar
  52. Gago G, Kurth D, Diacovich L, Tsai SC, Gramajo H (2006) Biochemical and structural characterization of an essential acyl coenzyme A carboxylase from Mycobacterium tuberculosis. J Bacteriol 188:477–486PubMedPubMedCentralCrossRefGoogle Scholar
  53. Galandrin S, Guillet V, Rane RS, Leger M, Radha N, Eynard N, Das K, Balganesh TS, Mourey L, Daffe M, Marrakchi H (2013) Assay development for identifying inhibitors of the mycobacterial FadD32 activity. J Biomol Screen 18:576–587PubMedCrossRefPubMedCentralGoogle Scholar
  54. Gande R, Gibson KJ, Brown AK, Krumbach K, Dover LG, Sahm H, Shioyama S, Oikawa T, Besra GS, Eggeling L (2004) Acyl-CoA carboxylases (accD2 and accD3), together with a unique polyketide synthase (Cg-pks), are key to mycolic acid biosynthesis in Corynebacterianeae such as Corynebacterium glutamicum and Mycobacterium tuberculosis. J Biol Chem 279:44847–44857PubMedCrossRefPubMedCentralGoogle Scholar
  55. Gannoun-Zaki L, Alibaud L, Kremer L (2013) Point mutations within the fatty acid synthase type II dehydratase components HadA or HadC contribute to isoxyl resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 57:629–632PubMedPubMedCentralCrossRefGoogle Scholar
  56. Gao LY, Laval F, Lawson EH, Groger RK, Woodruff A, Morisaki JH, Cox JS, Daffe M, Brown EJ (2003) Requirement for kasB in Mycobacterium mycolic acid biosynthesis, cell wall impermeability and intracellular survival: implications for therapy. Mol Microbiol 49:1547–1563PubMedCrossRefPubMedCentralGoogle Scholar
  57. Gavalda S, Leger M, van der Rest B, Stella A, Bardou F, Montrozier H, Chalut C, Burlet-Schiltz O, Marrakchi H, Daffe M, Quemard A (2009) The Pks13/FadD32 crosstalk for the biosynthesis of mycolic acids in Mycobacterium tuberculosis. J Biol Chem 284:19255–19264PubMedPubMedCentralCrossRefGoogle Scholar
  58. Gavalda S, Bardou F, Laval F, Bon C, Malaga W, Chalut C, Guilhot C, Mourey L, Daffe M, Quemard A (2014) The polyketide synthase Pks13 catalyzes a novel mechanism of lipid transfer in mycobacteria. Chem Biol 21:1660–1669PubMedCrossRefPubMedCentralGoogle Scholar
  59. Glickman MS (2008) Cording, cord factors, and trehalose dimycolate. In: Daffé M, Reyrat JM (eds) The mycobacterial cell envelope. ASM Press, Washington, DC, pp 63–73CrossRefGoogle Scholar
  60. Glickman MS, Cox JS, Jacobs WR Jr (2000) A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Mol Cell 5:717–727PubMedCrossRefPubMedCentralGoogle Scholar
  61. Glickman MS, Cahill SM, Jacobs WR (2001) The Mycobacterium tuberculosis cmaA2 gene encodes a mycolic acid trans-cyclopropane synthetase. J Biol Chem 276:2228–2233PubMedCrossRefPubMedCentralGoogle Scholar
  62. Goren MB, Brennan PJ (1979) Mycobacterial lipids: chemistry and biological activities. In: Youmans GP (ed) Tuberculosis. The WB Saunders Co, Philadelphia, pp 63–193Google Scholar
  63. Greenstein AE, Grundner C, Echols N, Gay LM, Lombana TN, Miecskowski CA, Pullen KE, Sung PY, Alber T (2005) Structure/function studies of Ser/Thr and Tyr protein phosphorylation in Mycobacterium tuberculosis. J Mol Microbiol Biotechnol 9:167–181PubMedCrossRefPubMedCentralGoogle Scholar
  64. Grzegorzewicz AE, Pham H, Gundi VA, Scherman MS, North EJ, Hess T, Jones V, Gruppo V, Born SE, Kordulakova J, Chavadi SS, Morisseau C, Lenaerts AJ, Lee RE, McNeil MR, Jackson M (2012a) Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat Chem Biol 8:334–341PubMedPubMedCentralCrossRefGoogle Scholar
  65. Grzegorzewicz AE, Kordulakova J, Jones V, Born SE, Belardinelli JM, Vaquie A, Gundi VA, Madacki J, Slama N, Laval F, Vaubourgeix J, Crew RM, Gicquel B, Daffe M, Morbidoni HR, Brennan PJ, Quemard A, McNeil MR, Jackson M (2012b) A common mechanism of inhibition of the Mycobacterium tuberculosis mycolic acid biosynthetic pathway by isoxyl and thiacetazone. J Biol Chem 287:38434–38441PubMedPubMedCentralCrossRefGoogle Scholar
  66. Grzegorzewicz AE, Eynard N, Quemard A, North EJ, Margolis A, Lindenberger JJ, Jones V, Kordulakova J, Brennan PJ, Lee RE, Ronning DR, McNeil MR, Jackson M (2015) Covalent modification of the FAS-II dehydratase by Isoxyl and Thiacetazone. ACS Infect Dis 1:91–97PubMedCrossRefPubMedCentralGoogle Scholar
  67. Guillet V, Galandrin S, Maveyraud L, Ladeveze S, Mariaule V, Bon C, Eynard N, Daffe M, Marrakchi H, Mourey L (2016) Insight into structure-function relationships and inhibition of the fatty acyl-AMP ligase (FadD32) orthologs from mycobacteria. J Biol Chem 291:7973–7989PubMedPubMedCentralCrossRefGoogle Scholar
  68. Halloum I, Carrere-Kremer S, Blaise M, Viljoen A, Bernut A, Le Moigne V, Vilcheze C, Guerardel Y, Lutfalla G, Herrmann JL, Jacobs WR Jr, Kremer L (2016) Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent. Proc Natl Acad Sci U S A 113:E4228–E4237PubMedPubMedCentralCrossRefGoogle Scholar
  69. Hanoulle X, Wieruszeski JM, Rousselot-Pailley P, Landrieu I, Locht C, Lippens G, Baulard AR (2006) Selective intracellular accumulation of the major metabolite issued from the activation of the prodrug ethionamide in mycobacteria. J Antimicrob Chemother 58:768–772PubMedCrossRefPubMedCentralGoogle Scholar
  70. Hoffmann C, Leis A, Niederweis M, Plitzko JM, Engelhardt H (2008) Disclosure of the mycobacterial outer membrane: cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc Natl Acad Sci U S A 105:3963–3967PubMedPubMedCentralCrossRefGoogle Scholar
  71. Hong S, Cheng TY, Layre E, Sweet L, Young DC, Posey JE, Butler WR, Moody DB (2012) Ultralong C100 mycolic acids support the assignment of Segniliparus as a new bacterial genus. PLoS One 7:e39017PubMedPubMedCentralCrossRefGoogle Scholar
  72. Hunter RL, Armitige L, Jagannath C, Actor JK (2009) TB research at UT-Houston – a review of cord factor: new approaches to drugs, vaccines and the pathogenesis of tuberculosis. Tuberculosis (Edinb) 89:S18–S25CrossRefGoogle Scholar
  73. Indrigo J, Hunter RL Jr, Actor JK (2002) Influence of trehalose 6,6′-dimycolate (TDM) during mycobacterial infection of bone marrow macrophages. Microbiology 148:1991–1998PubMedCrossRefPubMedCentralGoogle Scholar
  74. Indrigo J, Hunter RL Jr, Actor JK (2003) Cord factor trehalose 6,6′-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages. Microbiology 149:2049–2059PubMedCrossRefPubMedCentralGoogle Scholar
  75. Ioerger TR, O’Malley T, Liao R, Guinn KM, Hickey MJ, Mohaideen N, Murphy KC, Boshoff HI, Mizrahi V, Rubin EJ, Sassetti CM, Barry CE 3rd, Sherman DR, Parish T, Sacchettini JC (2013) Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. PLoS One 8:e75245PubMedPubMedCentralCrossRefGoogle Scholar
  76. Jackson M, Raynaud C, Laneelle MA, Guilhot C, Laurent-Winter C, Ensergueix D, Gicquel B, Daffe M (1999) Inactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope. Mol Microbiol 31:1573–1587PubMedCrossRefPubMedCentralGoogle Scholar
  77. Jamet S, Quentin Y, Coudray C, Texier P, Laval F, Daffe M, Fichant G, Cam K (2015a) Evolution of mycolic acid biosynthesis genes and their regulation during starvation in Mycobacterium tuberculosis. J Bacteriol 197:3797–3811PubMedPubMedCentralCrossRefGoogle Scholar
  78. Jamet S, Slama N, Domingues J, Laval F, Texier P, Eynard N, Quemard A, Peixoto A, Lemassu A, Daffe M, Cam K (2015b) The non-essential mycolic acid biosynthesis genes hadA and hadC contribute to the physiology and fitness of Mycobacterium smegmatis. PLoS One 10:e0145883PubMedPubMedCentralCrossRefGoogle Scholar
  79. Jarlier V, Nikaido H (1994) Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS Microbiol Lett 123:11–18PubMedCrossRefPubMedCentralGoogle Scholar
  80. Johnsson K, Shultz PG (1994) Mechanistic studies of the oxidation of isoniazid by the catalase peroxidase from Mycobacterium tuberculosis. J Am Chem Soc 116:7425–7426CrossRefGoogle Scholar
  81. Julian E, Roldan M, Sanchez-Chardi A, Astola O, Agusti G, Luquin M (2010) Microscopic cords, a virulence-related characteristic of Mycobacterium tuberculosis, are also present in nonpathogenic mycobacteria. J Bacteriol 192:1751–1760PubMedPubMedCentralCrossRefGoogle Scholar
  82. Kalscheuer R, Weinrick B, Veeraraghavan U, Besra GS, Jacobs WR Jr (2010) Trehalose-recycling ABC transporter LpqY-SugA-SugB-SugC is essential for virulence of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 107:21761–21766PubMedPubMedCentralCrossRefGoogle Scholar
  83. Kapilashrami K, Bommineni GR, Machutta CA, Kim P, Lai CT, Simmerling C, Picart F, Tonge PJ (2013) Thiolactomycin-based beta-ketoacyl-AcpM synthase A (KasA) inhibitors: fragment-based inhibitor discovery using transient one-dimensional nuclear overhauser effect NMR spectroscopy. J Biol Chem 288:6045–6052PubMedPubMedCentralCrossRefGoogle Scholar
  84. Kordulakova J, Janin YL, Liav A, Barilone N, Dos Vultos T, Rauzier J, Brennan PJ, Gicquel B, Jackson M (2007) Isoxyl activation is required for bacteriostatic activity against Mycobacterium tuberculosis. Antimicrob Agents Chemother 51:3824–3829PubMedPubMedCentralCrossRefGoogle Scholar
  85. Kremer L, Douglas JD, Baulard AR, Morehouse C, Guy MR, Alland D, Dover LG, Lakey JH, Jacobs WR Jr, Brennan PJ, Minnikin DE, Besra GS (2000) Thiolactomycin and related analogues as novel anti-mycobacterial agents targeting KasA and KasB condensing enzymes in Mycobacterium tuberculosis. J Biol Chem 275:16857–16864PubMedCrossRefPubMedCentralGoogle Scholar
  86. Kremer L, Dover LG, Carrere S, Nampoothiri KM, Lesjean S, Brown AK, Brennan PJ, Minnikin DE, Locht C, Besra GS (2002) Mycolic acid biosynthesis and enzymic characterization of the beta-ketoacyl-ACP synthase A-condensing enzyme from Mycobacterium tuberculosis. Biochem J 364:423–430PubMedPubMedCentralCrossRefGoogle Scholar
  87. Kremer L, Dover LG, Morbidoni HR, Vilcheze C, Maughan WN, Baulard A, Tu SC, Honore N, Deretic V, Sacchettini JC, Locht C, Jacobs WR Jr, Besra GS (2003) Inhibition of InhA activity, but not KasA activity, induces formation of a KasA-containing complex in mycobacteria. J Biol Chem 278:20547–22055PubMedCrossRefPubMedCentralGoogle Scholar
  88. La Rosa V, Poce G, Canseco JO, Buroni S, Pasca MR, Biava M, Raju RM, Porretta GC, Alfonso S, Battilocchio C, Javid B, Sorrentino F, Ioerger TR, Sacchettini JC, Manetti F, Botta M, De Logu A, Rubin EJ, De Rossi E (2012) MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212. Antimicrob Agents Chemother 56:324–331PubMedPubMedCentralCrossRefGoogle Scholar
  89. Laneelle MA, Laneelle G (1970) Structure of mycolic acids and an intermediate in the biosynthesis of dicarboxylic mycolic acids. Eur J Biochem 12:296–300PubMedCrossRefPubMedCentralGoogle Scholar
  90. Laneelle MA, Launay A, Spina L, Marrakchi H, Laval F, Eynard N, Lemassu A, Tropis M, Daffe M, Etienne G (2012) A novel mycolic acid species defines two novel genera of the Actinobacteria, Hoyosella and Amycolicicoccus. Microbiology 158:843–855PubMedCrossRefPubMedCentralGoogle Scholar
  91. Laneelle MA, Eynard N, Spina L, Lemassu A, Laval F, Huc E, Etienne G, Marrakchi H, Daffe M (2013) Structural elucidation and genomic scrutiny of the C60–C100 mycolic acids of Segniliparus rotundus. Microbiology 159:191–203PubMedCrossRefPubMedCentralGoogle Scholar
  92. Laneelle MA, Nigou J, Daffe M (2015) Lipid and lipoarabinomannan isolation and characterization. Methods Mol Biol 1285:77–103PubMedCrossRefPubMedCentralGoogle Scholar
  93. Laval F, Laneelle MA, Deon C, Monsarrat B, Daffe M (2001) Accurate molecular mass determination of mycolic acids by MALDI-TOF mass spectrometry. Anal Chem 73:4537–4544PubMedCrossRefPubMedCentralGoogle Scholar
  94. Laval F, Haites R, Movahedzadeh F, Lemassu A, Wong CY, Stoker N, Billman-Jacobe H, Daffe M (2008) Investigating the function of the putative mycolic acid methyltransferase UmaA: divergence between the Mycobacterium smegmatis and Mycobacterium tuberculosis proteins. J Biol Chem 283:1419–1427PubMedCrossRefPubMedCentralGoogle Scholar
  95. Layre E, Collmann A, Bastian M, Mariotti S, Czaplicki J, Prandi J, Mori L, Stenger S, De Libero G, Puzo G, Gilleron M (2009) Mycolic acids constitute a scaffold for mycobacterial lipid antigens stimulating CD1-restricted T cells. Chem Biol 16:82–92PubMedCrossRefPubMedCentralGoogle Scholar
  96. Le NH, Molle V, Eynard N, Miras M, Stella A, Bardou F, Galandrin S, Guillet V, Andre-Leroux G, Bellinzoni M, Alzari P, Mourey L, Burlet-Schiltz O, Daffe M, Marrakchi H (2016) Ser/Thr phosphorylation regulates the Fatty Acyl-AMP Ligase activity of FadD32, an essential enzyme in mycolic acid biosynthesis. J Biol Chem 291:22793–22805PubMedPubMedCentralCrossRefGoogle Scholar
  97. Lea-Smith DJ, Pyke JS, Tull D, McConville MJ, Coppel RL, Crellin PK (2007) The reductase that catalyzes mycolic motif synthesis is required for efficient attachment of mycolic acids to arabinogalactan. J Biol Chem 282:11000–11008PubMedCrossRefPubMedCentralGoogle Scholar
  98. Lederer E (1969) Some problems concerning biological C-alkylation reactions and phytosterol biosynthesis. Q Rev Chem Soc 23:453–481CrossRefGoogle Scholar
  99. Leger M, Gavalda S, Guillet V, van der Rest B, Slama N, Montrozier H, Mourey L, Quemard A, Daffe M, Marrakchi H (2009) The dual function of the Mycobacterium tuberculosis FadD32 required for mycolic acid biosynthesis. Chem Biol 16:510–519PubMedCrossRefPubMedCentralGoogle Scholar
  100. Li W, Upadhyay A, Fontes FL, North EJ, Wang Y, Crans DC, Grzegorzewicz AE, Jones V, Franzblau SG, Lee RE, Crick DC, Jackson M (2014) Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis. Antimicrob Agents Chemother 58:6413–6423PubMedPubMedCentralCrossRefGoogle Scholar
  101. Li W, Gu S, Fleming J, Bi L (2015) Crystal structure of FadD32, an enzyme essential for mycolic acid biosynthesis in mycobacteria. Sci Rep 5:15493PubMedPubMedCentralCrossRefGoogle Scholar
  102. Li W, Obregon-Henao A, Wallach JB, North EJ, Lee RE, Gonzalez-Juarrero M, Schnappinger D, Jackson M (2016) Therapeutic potential of the Mycobacterium tuberculosis mycolic acid transporter, MmpL3. Antimicrob Agents Chemother 60:5198–5207PubMedPubMedCentralCrossRefGoogle Scholar
  103. Liu J, Barry CE 3rd, Besra GS, Nikaido H (1996) Mycolic acid structure determines the fluidity of the mycobacterial cell wall. J Biol Chem 271:29545–29551PubMedCrossRefPubMedCentralGoogle Scholar
  104. Mann KM, Pride A, Flentie K, Kimmey J, Weiss L, Stallings C (2016) Analysis of the contribution of MTP and the predicted Flp pilus genes to Mycobacterium tuberculosis pathogenesis. Microbiology 162:1784–1796PubMedPubMedCentralCrossRefGoogle Scholar
  105. Marchand CH, Salmeron C, Bou Raad R, Meniche X, Chami M, Masi M, Blanot D, Daffe M, Tropis M, Huc E, Le Marechal P, Decottignies P, Bayan N (2012) Biochemical disclosure of the mycolate outer membrane of Corynebacterium glutamicum. J Bacteriol 194:587–597PubMedPubMedCentralCrossRefGoogle Scholar
  106. Marrakchi H, Laneelle G, Quemard A (2000) InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II. Microbiology 146:289–296PubMedCrossRefPubMedCentralGoogle Scholar
  107. Marrakchi H, Choi KH, Rock CO (2002) A new mechanism for anaerobic unsaturated fatty acid formation in Streptococcus pneumoniae. J Biol Chem 277:44809–44816CrossRefGoogle Scholar
  108. Marrakchi H, Laneelle MA, Daffe M (2014) Mycolic acids: structures, biosynthesis, and beyond. Chem Biol 21:67–85PubMedCrossRefPubMedCentralGoogle Scholar
  109. Mdluli K, Sherman DR, Hickey MJ, Kreiswirth BN, Morris S, Stover CK, Barry CE 3rd (1996) Biochemical and genetic data suggest that InhA is not the primary target for activated isoniazid in Mycobacterium tuberculosis. J Infect Dis 174:1085–1090PubMedCrossRefPubMedCentralGoogle Scholar
  110. Mitchison DA (1998) Basic concepts in the chemotherapy of tuberculosis. In: Gangadharam PRJ, Jenkins PA (ed) Mycobacteria: II chemotherapy. Chapman & Hall Medical Microbiology Series, Springer US, pp 15–43CrossRefGoogle Scholar
  111. Molle V, Kremer L (2010) Division and cell envelope regulation by Ser/Thr phosphorylation: Mycobacterium shows the way. Mol Microbiol 75:1064–1077PubMedCrossRefPubMedCentralGoogle Scholar
  112. Mondino S, Gago G, Gramajo H (2013) Transcriptional regulation of fatty acid biosynthesis in mycobacteria. Mol Microbiol 89:372–387PubMedPubMedCentralCrossRefGoogle Scholar
  113. Moody DB, Reinhold BB, Guy MR, Beckman EM, Frederique DE, Furlong ST, Ye S, Reinhold VN, Sieling PA, Modlin RL, Besra GS, Porcelli SA (1997) Structural requirements for glycolipid antigen recognition by CD1b-restricted T cells. Science 278:283–286PubMedCrossRefPubMedCentralGoogle Scholar
  114. Moody DB, Guy MR, Grant E, Cheng TY, Brenner MB, Besra GS, Porcelli SA (2000) CD1b-mediated T cell recognition of a glycolipid antigen generated from mycobacterial lipid and host carbohydrate during infection. J Exp Med 192:965–976PubMedPubMedCentralCrossRefGoogle Scholar
  115. Nikiforov PO, Surade S, et al (2016) A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters. Org Biomol Chem 14(7):2318–2326CrossRefGoogle Scholar
  116. North EJ, Jackson M, Lee RE (2014) New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics. Curr Pharm Des 20:4357–4378PubMedPubMedCentralCrossRefGoogle Scholar
  117. Odriozola JM, Ramos JA, Bloch K (1977) Fatty acid synthetase activity in Mycobacterium smegmatis. Characterization of the acyl carrier protein-dependent elongating system. Biochim Biophys Acta 488:207–217PubMedCrossRefPubMedCentralGoogle Scholar
  118. Oh TJ, Daniel J, Kim HJ, Sirakova TD, Kolattukudy PE (2006) Identification and characterization of Rv3281 as a novel subunit of a biotin-dependent acyl-CoA Carboxylase in Mycobacterium tuberculosis H37Rv. J Biol Chem 281:3899–3908PubMedCrossRefPubMedCentralGoogle Scholar
  119. Ojha A, Anand M, Bhatt A, Kremer L, Jacobs WR Jr, Hatfull GF (2005) GroEL1: a dedicated chaperone involved in mycolic acid biosynthesis during biofilm formation in mycobacteria. Cell 123:861–873PubMedCrossRefPubMedCentralGoogle Scholar
  120. Ojha AK, Baughn AD, Sambandan D, Hsu T, Trivelli X, Guerardel Y, Alahari A, Kremer L, Jacobs WR Jr, Hatfull GF (2008) Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harbouring drug-tolerant bacteria. Mol Microbiol 69:164–174PubMedPubMedCentralCrossRefGoogle Scholar
  121. Ojha AK, Trivelli X, Guerardel Y, Kremer L, Hatfull GF (2010) Enzymatic hydrolysis of trehalose dimycolate releases free mycolic acids during mycobacterial growth in biofilms. J Biol Chem 285:17380–17389PubMedPubMedCentralCrossRefGoogle Scholar
  122. Pacheco SA, Hsu FF, Powers KM, Purdy GE (2013) MmpL11 protein transports mycolic acid-containing lipids to the mycobacterial cell wall and contributes to biofilm formation in Mycobacterium smegmatis. J Biol Chem 288:24213–24222PubMedPubMedCentralCrossRefGoogle Scholar
  123. Parish T, Roberts G, Laval F, Schaeffer M, Daffe M, Duncan K (2007) Functional complementation of the essential gene fabG1 of Mycobacterium tuberculosis by Mycobacterium smegmatis fabG, but not Escherichia coli fabG. J Bacteriol 189:3721–3728PubMedPubMedCentralCrossRefGoogle Scholar
  124. Payne K, Sun Q, Sacchettini J, Hatfull GF (2009) Mycobacteriophage Lysin B is a novel mycolylarabinogalactan esterase. Mol Microbiol 73:367–381PubMedPubMedCentralCrossRefGoogle Scholar
  125. Peyron P, Vaubourgeix J, Poquet Y, Levillain F, Botanch C, Bardou F, Daffe M, Emile JF, Marchou B, Cardona PJ, de Chastellier C, Altare F (2008) Foamy macrophages from tuberculous patients’ granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence. PLoS Pathog 4:e1000204PubMedPubMedCentralCrossRefGoogle Scholar
  126. Phetsuksiri B, Jackson M, Scherman H, McNeil M, Besra GS, Baulard AR, Slayden RA, DeBarber AE, Barry CE 3rd, Baird MS, Crick DC, Brennan PJ (2003) Unique mechanism of action of the thiourea drug isoxyl on Mycobacterium tuberculosis. J Biol Chem 278:53123–53130PubMedPubMedCentralCrossRefGoogle Scholar
  127. Portevin D, De Sousa-D’Auria C, Houssin C, Grimaldi C, Chami M, Daffe M, Guilhot C (2004) A polyketide synthase catalyzes the last condensation step of mycolic acid biosynthesis in mycobacteria and related organisms. Proc Natl Acad Sci U S A 101:314–319PubMedCrossRefPubMedCentralGoogle Scholar
  128. Portevin D, de Sousa-D’Auria C, Montrozier H, Houssin C, Stella A, Laneelle MA, Bardou F, Guilhot C, Daffe M (2005) The acyl-AMP ligase FadD32 and AccD4-containing acyl-CoA carboxylase are required for the synthesis of mycolic acids and essential for mycobacterial growth: identification of the carboxylation product and determination of the acyl-CoA carboxylase components. J Biol Chem 280:8862–8874PubMedCrossRefPubMedCentralGoogle Scholar
  129. Puech V, Guilhot C, Perez E, Tropis M, Armitige LY, Gicquel B, Daffe M (2002) Evidence for a partial redundancy of the fibronectin-binding proteins for the transfer of mycoloyl residues onto the cell wall arabinogalactan termini of Mycobacterium tuberculosis. Mol Microbiol 44:1109–1122PubMedCrossRefPubMedCentralGoogle Scholar
  130. Purwantini E, Mukhopadhyay B (2013) Rv0132c of Mycobacterium tuberculosis encodes a coenzyme F420-dependent hydroxymycolic acid dehydrogenase. PLoS One 8:e81985PubMedPubMedCentralCrossRefGoogle Scholar
  131. Queiroz A, Medina-Cleghorn D, Marjanovic O, Nomura DK, Riley LW (2015) Comparative metabolic profiling of mce1 operon mutant vs wild-type Mycobacterium tuberculosis strains. Pathog Dis 73:ftv066PubMedPubMedCentralCrossRefGoogle Scholar
  132. Quemard A (2016) New insights into the mycolate-containing compound biosynthesis and transport in mycobacteria. Trends Microbiol 24:725–738PubMedCrossRefPubMedCentralGoogle Scholar
  133. Quemard A, Lacave C, Laneelle G (1991) Isoniazid inhibition of mycolic acid synthesis by cell extracts of sensitive and resistant strains of Mycobacterium aurum. Antimicrob Agents Chemother 35:1035–1039PubMedPubMedCentralCrossRefGoogle Scholar
  134. Quemard A, Sacchettini JC, Dessen A, Vilcheze C, Bittman R, Jacobs WR Jr, Blanchard JS (1995) Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry (Mosc) 34:8235–8241CrossRefGoogle Scholar
  135. Quémard A, Dessen A, Sugantino M, Jacobs WR Jr, Sacchettini JC, Blanchard JS (1996) Binding of catalase-peroxidase-activated isoniazid to wild-type and mutant Mycobacterium tuberculosis enoyl-ACP reductases. J Am Chem Soc 118:1561–1562CrossRefGoogle Scholar
  136. Qureshi N, Sathyamoorthy N, Takayama K (1984) Biosynthesis of C30 to C56 fatty acids by an extract of Mycobacterium tuberculosis H37Ra. J Bacteriol 157:46–52PubMedPubMedCentralGoogle Scholar
  137. Rafidinarivo E, Prome JC, Levy-Frebault V (1985) New kinds of unsaturated mycolic acids from Mycobacterium fallax sp. nov. Chem Phys Lipids 36:215–228CrossRefGoogle Scholar
  138. Ramesh R, Shingare RD, Kumar V, Anand ABS, Veeraraghavan S, Viswanadha S, Ummanni R, Gokhale R, Srinivasa Reddy D (2016) Repurposing of a drug scaffold: identification of novel sila analogues of rimonabant as potent antitubercular agents. Eur J Med Chem 122:723–730PubMedCrossRefPubMedCentralGoogle Scholar
  139. Rao V, Gao F, Chen B, Jacobs WR Jr, Glickman MS (2006) Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis -induced inflammation and virulence. J Clin Invest 116:1660–1667PubMedPubMedCentralCrossRefGoogle Scholar
  140. Rehm HJ, Reiff I (1981) Mechanisms and occurence of microbial oxidation of long-chain alkanes. Adv Biochem Eng 19:175–215Google Scholar
  141. Rock CO, Cronan JE (1996) Escherichia coli as a model for the regulation of dissociable (type II) fatty acid biosynthesis. Biochim Biophys Acta 1302:1–16PubMedCrossRefPubMedCentralGoogle Scholar
  142. Rombouts Y, Brust B, Ojha AK, Maes E, Coddeville B, Elass-Rochard E, Kremer L, Guerardel Y (2012) Exposure of mycobacteria to cell wall-inhibitory drugs decreases production of arabinoglycerolipid related to Mycolyl-arabinogalactan-peptidoglycan metabolism. J Biol Chem 287:11060–11069PubMedPubMedCentralCrossRefGoogle Scholar
  143. Rozwarski DA, Grant GA, Barton DH, Jacobs WR Jr, Sacchettini JC (1998) Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. Science 279:98–102PubMedCrossRefPubMedCentralGoogle Scholar
  144. Sacco E, Covarrubias AS, O’Hare HM, Carroll P, Eynard N, Jones TA, Parish T, Daffe M, Backbro K, Quemard A (2007) The missing piece of the type II fatty acid synthase system from Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 104:14628–14633PubMedPubMedCentralCrossRefGoogle Scholar
  145. Salzman V, Mondino S, Sala C, Cole ST, Gago G, Gramajo H (2010) Transcriptional regulation of lipid homeostasis in mycobacteria. Mol Microbiol 78:64–77PubMedPubMedCentralGoogle Scholar
  146. Sambandan D, Dao DN, Weinrick BC, Vilcheze C, Gurcha SS, Ojha A, Kremer L, Besra GS, Hatfull GF, Jacobs WR Jr (2013) Keto-mycolic acid-dependent pellicle formation confers tolerance to drug-sensitive Mycobacterium tuberculosis. MBio 4:e00222–13PubMedPubMedCentralCrossRefGoogle Scholar
  147. Sani M, Houben EN, Geurtsen J, Pierson J, de Punder K, van Zon M, Wever B, Piersma SR, Jimenez CR, Daffe M, Appelmelk BJ, Bitter W, van der Wel N, Peters PJ (2010) Direct visualization by cryo-EM of the mycobacterial capsular layer: a labile structure containing ESX-1-secreted proteins. PLoS Pathog 6:e1000794PubMedPubMedCentralCrossRefGoogle Scholar
  148. Schaeffer ML, Agnihotri G, Volker C, Kallender H, Brennan PJ, Lonsdale JT (2001) Purification and biochemical characterization of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthases KasA and KasB. J Biol Chem 276:47029–47037PubMedCrossRefPubMedCentralGoogle Scholar
  149. Singh A, Varela C, Bhatt K, Veerapen N, Lee OY, Wu HH, Besra GS, Minnikin DE, Fujiwara N, Teramoto K, Bhatt A (2016) Identification of a desaturase involved in mycolic acid biosynthesis in Mycobacterium smegmatis. PLoS One 11:e0164253PubMedPubMedCentralCrossRefGoogle Scholar
  150. Sinha BK (1983) Enzymatic activation of hydrazine derivatives. A spin-trapping study. J Biol Chem 258:796–801PubMedPubMedCentralGoogle Scholar
  151. Slama N, Leiba J, Eynard N, Daffe M, Kremer L, Quemard A, Molle V (2011) Negative regulation by Ser/Thr phosphorylation of HadAB and HadBC dehydratases from Mycobacterium tuberculosis type II fatty acid synthase system. Biochem Biophys Res Commun 412:401–406PubMedCrossRefPubMedCentralGoogle Scholar
  152. Slama N, Jamet S, Frigui W, Pawlik A, Bottai D, Laval F, Constant P, Lemassu A, Cam K, Daffe M, Brosch R, Eynard N, Quemard A (2016) The changes in mycolic acid structures caused by hadC mutation have a dramatic effect on the virulence of Mycobacterium tuberculosis. Mol Microbiol 99:794–807PubMedCrossRefPubMedCentralGoogle Scholar
  153. Stanley SA, Kawate T, Iwase N, Shimizu M, Clatworthy AE, Kazyanskaya E, Sacchettini JC, Ioerger TR, Siddiqi NA, Minami S, Aquadro JA, Schmidt Grant S, Rubin EJ, Hung DT (2013) Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32. Proc Natl Acad Sci U S A 110:11565–11570PubMedPubMedCentralCrossRefGoogle Scholar
  154. Stec J, Onajole OK, Lun S, Guo H, Merenbloom B, Vistoli G, Bishai WR, Kozikowski AP (2016) Indole-2-carboxamide-based MmpL3 inhibitors show exceptional antitubercular activity in an animal model of tuberculosis infection. J Med Chem 59:6232–6247PubMedCrossRefPubMedCentralGoogle Scholar
  155. Tahlan K, Wilson R, Kastrinsky DB, Arora K, Nair V, Fischer E, Barnes SW, Walker JR, Alland D, Barry CE 3rd, Boshoff HI (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 56:1797–1809PubMedPubMedCentralCrossRefGoogle Scholar
  156. Takayama K, Qureshi N (1978) Isolation and characterization of the monounsaturated long chain fatty acids of Mycobacterium tuberculosis. Lipids 13:575–579PubMedCrossRefPubMedCentralGoogle Scholar
  157. Takayama K, Wang L, David HL (1972) Effect of isoniazid on the in vivo mycolic acid synthesis, cell growth, and viability of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2:29–35PubMedPubMedCentralCrossRefGoogle Scholar
  158. Takayama K, Wang C, Besra GS (2005) Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin Microbiol Rev 18:81–101PubMedPubMedCentralCrossRefGoogle Scholar
  159. Tang X, Deng W, Xie J (2012) Novel insights into Mycobacterium antigen Ag85 biology and implications in countermeasures for M. tuberculosis. Crit Rev Eukaryot Gene Expr 22:179–187PubMedCrossRefPubMedCentralGoogle Scholar
  160. Tarnok I, Rohrscheidt E (1976) Biochemical background of some enzymatic tests used for the differentiation of mycobacteria. Tubercle 57:145–150PubMedCrossRefPubMedCentralGoogle Scholar
  161. Tomiyasu I, Yano I (1984) Separation and analysis of novel polyunsaturated mycolic acids from a psychrophilic, acid-fast bacterium, Gordona aurantiaca. Eur J Biochem 139:173–180PubMedCrossRefPubMedCentralGoogle Scholar
  162. Toriyama S, Izaizumi S, Tomiyasu I, Masui M, Yano I (1982) Incorporation of 18O into long-chain secondary alkohols derived from ester mycolic acids in Mycobacterium phlei. Biochim Biophys Acta 712:427–429CrossRefGoogle Scholar
  163. Trivedi OA, Arora P, Sridharan V, Tickoo R, Mohanty D, Gokhale RS (2004) Enzymic activation and transfer of fatty acids as acyl-adenylates in mycobacteria. Nature 428:441–445PubMedCrossRefPubMedCentralGoogle Scholar
  164. Uchida Y, Casali N, White A, Morici L, Kendall LV, Riley LW (2007) Accelerated immunopathological response of mice infected with Mycobacterium tuberculosis disrupted in the mce1 operon negative transcriptional regulator. Cell Microbiol 9:1275–1283PubMedCrossRefPubMedCentralGoogle Scholar
  165. Vander Beken S, Al Dulayymi JR, et al (2011) Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern. Eur J Immunol 41(2):450–460PubMedCrossRefPubMedCentralGoogle Scholar
  166. Varela C, Rittmann D, Singh A, Krumbach K, Bhatt K, Eggeling L, Besra GS, Bhatt A (2012) MmpL genes are associated with mycolic acid metabolism in mycobacteria and corynebacteria. Chem Biol 19:498–506PubMedPubMedCentralCrossRefGoogle Scholar
  167. Vergne I, Daffe M (1998) Interaction of mycobacterial glycolipids with host cells. Front Biosci 3:d865–d876PubMedCrossRefPubMedCentralGoogle Scholar
  168. Verschoor JA, Baird MS, Grooten J (2012) Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis. Prog Lipid Res 51:325–339PubMedCrossRefPubMedCentralGoogle Scholar
  169. Veyron-Churlet R, Guerrini O, Mourey L, Daffe M, Zerbib D (2004) Protein-protein interactions within the Fatty Acid Synthase-II system of Mycobacterium tuberculosis are essential for mycobacterial viability. Mol Microbiol 54:1161–1172PubMedCrossRefPubMedCentralGoogle Scholar
  170. Veyron-Churlet R, Bigot S, Guerrini O, Verdoux S, Malaga W, Daffe M, Zerbib D (2005) The biosynthesis of mycolic acids in Mycobacterium tuberculosis relies on multiple specialized elongation complexes interconnected by specific protein-protein interactions. J Mol Biol 353:847–858PubMedCrossRefPubMedCentralGoogle Scholar
  171. Vilcheze C, Morbidoni HR, Weisbrod TR, Iwamoto H, Kuo M, Sacchettini JC, Jacobs WR Jr (2000) Inactivation of the inhA-encoded fatty acid synthase II (FASII) enoyl-acyl carrier protein reductase induces accumulation of the FASI end products and cell lysis of Mycobacterium smegmatis. J Bacteriol 182:4059–4067PubMedPubMedCentralCrossRefGoogle Scholar
  172. Vilcheze C, Molle V, Carrere-Kremer S, Leiba J, Mourey L, Shenai S, Baronian G, Tufariello J, Hartman T, Veyron-Churlet R, Trivelli X, Tiwari S, Weinrick B, Alland D, Guerardel Y, Jacobs WR Jr, Kremer L (2014) Phosphorylation of KasB regulates virulence and acid-fastness in Mycobacterium tuberculosis. PLoS Pathog 10:e1004115PubMedPubMedCentralCrossRefGoogle Scholar
  173. Villeneuve M, Kawai M, Kanashima H, Watanabe M, Minnikin DE, Nakahara H (2005) Temperature dependence of the Langmuir monolayer packing of mycolic acids from Mycobacterium tuberculosis. Biochim Biophys Acta 1715:71–80PubMedCrossRefPubMedCentralGoogle Scholar
  174. Villeneuve M, Kawai M, Watanabe M, Aoyagi Y, Hitotsuyanagi Y, Takeya K, Gouda H, Hirono S, Minnikin DE, Nakahara H (2007) Conformational behavior of oxygenated mycobacterial mycolic acids from Mycobacterium bovis BCG. Biochim Biophys Acta 1768:1717–1726PubMedCrossRefPubMedCentralGoogle Scholar
  175. Villeneuve M, Kawai M, Horiuchi K, Watanabe M, Aoyagi Y, Hitotsuyanagi Y, Takeya K, Gouda H, Hirono S, Minnikin DE (2013) Conformational folding of mycobacterial methoxy- and ketomycolic acids facilitated by alpha-methyl trans-cyclopropane groups rather than cis-cyclopropane units. Microbiology 159:2405–2415PubMedCrossRefPubMedCentralGoogle Scholar
  176. Wang F, Langley R, Gulten G, Dover LG, Besra GS, Jacobs WR Jr, Sacchettini JC (2007) Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med 204:73–78PubMedPubMedCentralCrossRefGoogle Scholar
  177. Wang XM, Lu C, Soetaert K, S’Heeren C, Peirs P, Laneelle MA, Lefevre P, Bifani P, Content J, Daffe M, Huygen K, De Bruyn J, Wattiez R (2011) Biochemical and immunological characterization of a cpn60.1 knockout mutant of Mycobacterium bovis BCG. Microbiology 157:1205–1219PubMedCrossRefPubMedCentralGoogle Scholar
  178. Warrier T, Tropis M, Werngren J, Diehl A, Gengenbacher M, Schlegel B, Schade M, Oschkinat H, Daffe M, Hoffner S, Eddine AN, Kaufmann SH (2012) Antigen 85C inhibition restricts Mycobacterium tuberculosis growth through disruption of cord factor biosynthesis. Antimicrob Agents Chemother 56:1735–1743PubMedPubMedCentralCrossRefGoogle Scholar
  179. Watanabe M, Aoyagi Y, Ridell M, Minnikin DE (2001) Separation and characterization of individual mycolic acids in representative mycobacteria. Microbiology 147:1825–1837PubMedCrossRefPubMedCentralGoogle Scholar
  180. Wehenkel A, Bellinzoni M, Grana M, Duran R, Villarino A, Fernandez P, Andre-Leroux G, England P, Takiff H, Cervenansky C, Cole ST, Alzari PM (2008) Mycobacterial Ser/Thr protein kinases and phosphatases: physiological roles and therapeutic potential. Biochim Biophys Acta 1784:193–202PubMedCrossRefPubMedCentralGoogle Scholar
  181. Wilson R, Kumar P, Parashar V, Vilcheze C, Veyron-Churlet R, Freundlich JS, Barnes SW, Walker JR, Szymonifka MJ, Marchiano E, Shenai S, Colangeli R, Jacobs WR Jr, Neiditch MB, Kremer L, Alland D (2013) Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nat Chem Biol 9:499–506PubMedPubMedCentralCrossRefGoogle Scholar
  182. Winder FG (1982) Mode of action of the antimycobacterial agents and associated aspects of the molecular biology of the mycobacteria. In: Ratledge C, Stanford J (eds) The biology of the mycobacteria. Academic, London, pp 354–438Google Scholar
  183. Wong MY, Gray GR (1979) Structures of the homologous series of monoalkene mycolic acids from Mycobacterium smegmatis. J Biol Chem 254:5741–5744PubMedPubMedCentralGoogle Scholar
  184. Yuan Y, Barry CE (1996) A common mechanism for the biosynthesis of methoxy and cyclopropyl mycolic acids in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 93:12828–12833PubMedPubMedCentralCrossRefGoogle Scholar
  185. Yuan Y, Mead D, Schroeder BG, Zhu Y, Barry CE 3rd (1998) The biosynthesis of mycolic acids in Mycobacterium tuberculosis. Enzymatic methyl(ene) transfer to acyl carrier protein bound meromycolic acid in vitro. J Biol Chem 273:21282–21290PubMedCrossRefPubMedCentralGoogle Scholar
  186. Zhang Y, Heym B, Allen B, Young D, Cole S (1992) The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358:591–593PubMedCrossRefPubMedCentralGoogle Scholar
  187. Zuber B, Chami M, Houssin C, Dubochet J, Griffiths G, Daffe M (2008) Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. J Bacteriol 190:5672–5680PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Mamadou Daffé
    • 1
    Email author
  • Annaïk Quémard
    • 1
  • Hedia Marrakchi
    • 1
  1. 1.Institut de Pharmacologie et de Biologie StructuraleUniversité de Toulouse, CNRS, UPSToulouseFrance

Personalised recommendations