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Chemical Synthesis of Lipopolysaccharide Core

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Bacterial Lipopolysaccharides

Abstract

Genomic data and analytical studies of the past decade have revealed a multitude of novel structural features of the core region of the lipopolysaccharide of Gram-negative bacteria. The chapter presents an update of ongoing and recent synthetic efforts illustrating representative examples for the synthesis of complex oligosaccharides as ligands, structural analogues as well as neoglycoconjugates. A major focus has been placed on chemical and chemo-enzymatic synthesis of the higher-carbon sugars 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) as well L-glycero-D-manno-heptose followed by subsequent conversion into suitable glycosyl donors and acceptor derivatives for the assembly of inner and outer core units. Major synthetic accomplishments covering core structures from Chlamydia, Burkholderia, Proteus, Haemophilus, Nesseria, Escherichia coli and Pseudomonas aeruginosa LPS are described in this review.

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References

  1. Holst O (2007) The structures of core regions from enterobacterial lipopolysaccharides – an update. FEMS Microbiol Lett 271:3–11

    Article  CAS  Google Scholar 

  2. Hansson J, Oscarson S (2000) Complex bacterial carbohydrate surface antigen structures: syntheses of Kdo- and heptose-containing lipopolysaccharide core structures and anomerically linked phosphodiester-linked oligosaccharide structures. Curr Org Chem 4:535–564

    Article  CAS  Google Scholar 

  3. Kosma P (2009) Chemical synthesis of the core oligosaccharide of bacterial lipopolysaccharide. In: Moran A, Brennan P, Holst O, von Itzstein M (eds) Microbial glycobiology: structures, relevance and applications. Elsevier, San Diego, pp 429–454

    Google Scholar 

  4. Oscarson S (1997) Synthesis of oligosaccharides of bacterial origin containing heptoses, uronic acids and fructofuranoses as synthetic challenges. Top Curr Chem 186:171–202

    Article  CAS  Google Scholar 

  5. Pozsgay V (2003) Chemical synthesis of bacterial carbohydrates. In: Wong SYC, Arsequell G (eds) Immunobiology of carbohydrates. Kluwer Academic/Plenum Publishers, New York, pp 192–273

    Google Scholar 

  6. Pozsgay V (2008) Recent developments in synthetic oligosaccharide-based bacterial vaccines. Curr Top Med Chem 8:126–140

    Article  CAS  Google Scholar 

  7. Li LS, Wu YL (2003) Recent progress in the syntheses of higher 3-deoxy-octulosonic acids and their derivatives. Curr Org Chem 7:447–475

    Article  CAS  Google Scholar 

  8. Kuboki A, Tajimi T, Tokuda Y, Kato Di, Sugai T, Ohira S (2004) Concise synthesis of 3-deoxy-d-manno-oct-2-ulosonic acid (KDO) as a protected form based on a new transformation of α,β-unsaturated ester to α-oxocarboxylic acid ester via diol cyclic sulfite. Tetrahedron Lett 45:4545–4548

    Article  CAS  Google Scholar 

  9. Kikelj V, Plantier-Royon R, Portella C (2006) A new short and efficient route to 3-deoxy-d-manno-oct-2-ulosonic acid (KDO) and 3-deoxy-d-arabino-hept-2-ulosonic acid (DAH). Synthesis 1200–1204

    Google Scholar 

  10. Hekking KFW, van Delft FL, Rutjes FPJT (2003) Ring-closing metathesis of α-substituted enol ethers: application to the shortest synthesis of KDO. Tetrahedron 59:6751–6758

    Article  CAS  Google Scholar 

  11. Hekking KFW, Moelands MAH, van Delft FL, Rutjes FPJT (2006) An in-depth study on ring-closing metathesis of carbohydrate-derived α-alkoxyacrylates: efficient syntheses of DAH, KDO, and 2-deoxy-β-KDO. J Org Chem 71:6444–6450

    Article  CAS  Google Scholar 

  12. Sugisaki CH, Ruland Y, Baltas M (2003) Direct access to furanosidic eight-membered ulosonic esters from cis-α,β-epoxy aldehydes. Eur J Org Chem 672–688

    Article  Google Scholar 

  13. Kim BG, Schilde U, Linker T (2005) New radical approaches to 3-deoxy-d-oct-2-ulosonic acids (KDO). Synthesis 1507–1513

    Google Scholar 

  14. Railton CJ, Clive DLJ (1996) Wittig chain extension of unprotected carbohydrates: formation of carbohydrate-derived α,β-unsaturated esters. Carbohydr Res 281:69–77

    Article  CAS  Google Scholar 

  15. Ichiyanagi T, Sakamoto N, Ochi K, Yamasaki R (2009) A chemical synthesis of 3-deoxy-d-manno-2-octulosonic acid from d-mannose. J Carbohydr Chem 28:53–63

    Article  CAS  Google Scholar 

  16. Winzar R, Philips J, Kiefel MJA (2010) Simple synthesis of C-8 modified 2-keto-3-deoxy-d-manno-octulosonic acid (KDO) derivatives. Synlett 583–586

    Article  Google Scholar 

  17. Sugai T, Shen GJ, Ichikawa Y, Wong CH (1993) Synthesis of 3-deoxy-d-manno-2-octulosonic acid (KDO) and its analogs based on KDO aldolase-catalyzed reactions. J Am Chem Soc 115:413–421

    Article  CAS  Google Scholar 

  18. Lamble HJ, Royer SF, Hough DW, Danson MJ, Taylor GL, Bull SDA (2007) Thermostable aldolase for the synthesis of 3-deoxy-2-ulosonic acids. Adv Synth Catal 349:817–821

    Article  CAS  Google Scholar 

  19. Dean SM, Greenberg WA, Wong C-H (2010) Recent advances in aldolase-catalyzed asymmetric synthesis. Adv Synth Catal 349:1308–1320

    Article  Google Scholar 

  20. Guerard C, Demuynck C, Bolte J (1999) Enzymatic synthesis of 3-deoxy-d-manno-2-octulosonic acid and analogues: a new approach by a non metabolic pathway. Tetrahedron Lett 40:4181–4182

    Article  CAS  Google Scholar 

  21. Crestia D, Demuynck C, Bolte J (2004) Transketolase and fructose-1,6-bisphosphate aldolase, complementary tools for access to new ulosonic acid analogues. Tetrahedron 60:2417–2425

    Article  CAS  Google Scholar 

  22. Gillingham DG, Stallforth P, Adibekian A, Seeberger PH, Hilvert D (2010) Chemoenzymatic synthesis of differentially protected 3-deoxysugars. Nat Chem 2:102–105

    Article  CAS  Google Scholar 

  23. Fujimoto Y, Iwata M, Imakita N, Shimoyama A, Suda Y, Kusumoto S, Fukase K (2007) Synthesis of immunoregulatory Helicobacter pylori lipopolysaccharide partial structures. Tetrahedron Lett 48:6577–6581

    Article  CAS  Google Scholar 

  24. Mannerstedt K, Ekelöf K, Oscarson S (2007) Evaluation of Kdo as glycosyl donors. Carbohydr Res 342:631–637

    Article  CAS  Google Scholar 

  25. Gronow S, Lindner B, Brade H, Müller-Loennies S (2008) Kdo-(2 → 8)-Kdo-(2 → 4)-Kdo but not Kdo-(2 → 4)-Kdo-(2 → 4)-Kdo is an acceptor for transfer of l-glycero-α-d-manno-heptose by Escherichia coli heptosyltransferase I (WaaC). Innate Immun 15:13–23

    Article  Google Scholar 

  26. Rund S, Lindner B, Brade H, Holst O (2000) Structural analysis of the lipopolysaccharide from Chlamydophila psittaci strain 6BC. Eur J Biochem 267:5717–5726

    Article  CAS  Google Scholar 

  27. Kosma P, Brade H, Evans S (2008) Lipopolysaccharide antigens of Chlamydia. In: Roy R (ed) Carbohydrate-based vaccines, vol 989, ACS symposium series. American Chemical Society, Washington DC, pp 239–257

    Chapter  Google Scholar 

  28. Müller-Loennies S, MacKenzie R, Patenaude SI, Evans SV, Kosma P, Brade H, Brade L, Narang S (2000) Characterization of high affinity monoclonal antibodies specific for chlamydial lipopolysaccharide. Glycobiology 10:121–130

    Article  Google Scholar 

  29. Nguyen HP, Seto NOL, MacKenzie CR, Brade L, Kosma P, Brade H, Evans SV (2003) Murine germline antibodies recognize multiple carbohydrate epitopes by flexible utilization of binding site residues. Nat Struct Biol 10:1019–1025

    Article  CAS  Google Scholar 

  30. Brooks CL, Müller-Loennies S, Brade L, Kosma P, Hirama T, MacKenzie CR, Brade H, Evans SV (2008) Exploration of specificity in germline monoclonal antibody recognition of a range of natural and synthetic epitopes. J Mol Biol 377:450–468

    Article  CAS  Google Scholar 

  31. Brooks CL, Müller-Loennies S, Borisova SN, Brade L, Kosma P, Hirama T, MacKenzie CR, Brade H, Evans SV (2010) Antibodies raised against chlamydial lipopolysaccharide antigens reveal convergence in germline gene usage and differential epitope recognition. Biochemistry 49:570–581

    Article  CAS  Google Scholar 

  32. Sixta G, Wimmer K, Hofinger A, Brade H, Kosma P (2009) Synthesis and antigenic properties of C-7-modified Kdo mono- and disaccharide ligands and Kdo disaccharide interresidue lactones. Carbohydr Res 344:1660–1669

    Article  CAS  Google Scholar 

  33. Brooks CL, Blackler RJ, Sixta G, Kosma P, Müller-Loennies S, Brade L, Hirama T, MacKenzie CR, Brade H, Evans SV (2010) The role of CDR H3 in antibody recognition of a synthetic analogue of a lipopolysaccharide antigen. Glycobiology 20:148–157

    Article  Google Scholar 

  34. Sixta G, Hofinger A, Kosma P (2007) Synthesis of spacer-containing chlamydial disaccharides as analogues of the α-Kdop-(2 → 8)-α-Kdop-(2 → 4)-α-Kdop trisaccharide epitope. Carbohydr Res 342:576–585

    Article  CAS  Google Scholar 

  35. Mikol V, Kosma P, Brade H (1994) Crystal and molecular structure of allyl O-(sodium 3-deoxy-α-d-manno-2-octulopyranosylonate)-(2 → 8)-O-(sodium 3-deoxy-α-d-manno-2-octulopyranosidonate)-monohydrate. Carbohydr Res 263:35–42

    Article  CAS  Google Scholar 

  36. Pudelko M, Lindgren A, Tengel T, Reis CA, Elofsson M, Kihlberg J (2006) Formation of lactones from sialylated MUC1 glycopeptides. Org Biomol Chem 4:713–720

    Article  CAS  Google Scholar 

  37. Cheng M-C, Lin C-H, Khoo K-H, Wu S-H (1999) Regioselective lactonization of α-(2 → 8)-trisialic acid. Angew Chem Int Ed Engl 38:686–689

    Article  CAS  Google Scholar 

  38. Müller-Loennies S, Gronow S, Brade L, MacKenzie R, Kosma P, Brade H (2006) A monoclonal antibody that recognizes an epitope present in the lipopolysaccharide of Chlamydiales differentiates Chlamydophila psittaci 6BC from Chlamydophila pneumoniae and Chlamydia trachomatis. Glycobiology 16:184–196

    Article  Google Scholar 

  39. Kosma P, Hofinger A, Müller-Loennies S, Brade H (2010) Synthesis of a neoglycoconjugate containing a Chlamydophila psittaci-specific branched Kdo trisaccharide epitope. Carbohydr Res 345:704–708

    Article  CAS  Google Scholar 

  40. Tanaka H, Takahashi D, Takahashi T (2006) Stereoselective synthesis of oligo-α(2,8)-3-deoxy-d-manno-2-octulosonic acid derivatives. Angew Chem Int Ed Engl 45:770–773

    Article  CAS  Google Scholar 

  41. Gerstenbruch S, Brooks CL, Kosma P, Brade L, MacKenzie CR, Evans SV, Brade H, Müller-Loennies S (2010) Analysis of cross-reactive and specific anti-carbohydrate antibodies against lipopolysaccharide from Chlamydophila psittaci. Glycobiology 20:461–472

    Article  CAS  Google Scholar 

  42. Sidorczyk Z, Kaca W, Brade H, Rietschel ET, Sinnwell V, Zähringer U (1987) Isolation and structural characterization of an 8-O-(4-amino-4-deoxy-β-l-arabinosyl)-3-deoxy-d-manno-octulosonic acid disaccharide in the lipopolysaccharide of a Proteus mirabilis deep rough mutant. Eur J Biochem 168:269–273

    Article  CAS  Google Scholar 

  43. Vinion-Dubiel AD, Goldberg JB (2003) Lipopolysaccharide of Burkholderia cepacia complex. J Endotoxin Res 9:201–213

    CAS  Google Scholar 

  44. De Soyza A, Silipo A, Lanzetta R, Govan JR, Molinaro A (2008) Chemical and biological features of Burkholderia cepacia lipopolysaccharides. Innate Immun 14:127–144

    Article  Google Scholar 

  45. Isshiki Y, Kawahara K, Zähringer U (1998) Isolation and characterization of disodium (4-amino-4-deoxy-β-l-arabinosyl)-(1 → 8)-(d-glycero-d-talo-2-octulosonate)-(2 → 4)-(methyl 3-deoxy-d-manno-2-octulopyranosid)onate from the lipopolysaccharide of Burkholderia cepacia. Carbohydr Res 313:21–27

    Article  CAS  Google Scholar 

  46. Vinogradov E, Lindner B, Seltmann G, Radziejewska-Lebrecht J, Holst O (2006) Lipopolysaccharides from Serratia marcescens possess one or two 4-amino-4-deoxy-l-arabinopyranose 1-phosphate residues in the lipid A and d-glycero-d-talo-oct-2-ulosonic acid in the inner core region. Chem Eur J 12:6692–6700

    Article  CAS  Google Scholar 

  47. Müller B, Blaukopf M, Hofinger A, Zamyatina A, Brade H, Kosma P (2010) Efficient synthesis of 4-amino-4-deoxy-l-arabinose and of spacer-equipped 4-amino-4-deoxy-l-arabinopyranosides by transglycosylation. Synthesis 3143–3151

    Article  Google Scholar 

  48. Blaukopf M, Müller B, Brade H, Kosma P (2010) Chemical synthesis of the inner core of Burkholderia LPS. In: Abstracts of the 25th international carbohydrate symposium, Tokyo, Japan, 2–6 Aug 2010

    Google Scholar 

  49. Kosma P (2008) Occurrence, synthesis and biosynthesis of bacterial heptoses. Curr Org Chem 12:1021–1039

    Article  CAS  Google Scholar 

  50. Gurjar MK, Talukdar A (2004) Synthesis of the terminal disaccharide unit of Klebsiella pneumoniae ssp. R20. Tetrahedron 60:3267–3271

    Article  CAS  Google Scholar 

  51. Crich D, Banerjee A (2005) Synthesis and stereoselective glycosylation of d- and L-glycero-β-d-manno-heptopyranoses. Org Lett 7:1395–1398

    Article  CAS  Google Scholar 

  52. Jaipuri FA, Collet YM, Pohl NL (2008) Synthesis and quantitative evaluation of glycero-d-manno-heptose binding to concanavalin A by fluorous-tag assistance. Angew Chem Int Ed Engl 47:1707–1710

    Article  CAS  Google Scholar 

  53. Bernlind C, Oscarson S (1997) Synthesis of d-glycero-d-manno-heptopyranose-containing oligosaccharide structures found in lipopolysaccharides from Haemophilus influenzae. Carbohydr Res 297:251–260

    Article  CAS  Google Scholar 

  54. Bernlind C, Oscarson S (1998) Synthesis of a branched heptose- and Kdo-containing common tetrasaccharide core structure of Haemophilus influenzae lipopolysaccharides via a 1,6-anhydro-l-glycero-β-d-manno-heptopyranose intermediate. J Org Chem 63:7780–7788

    Article  CAS  Google Scholar 

  55. Bernlind C, Bennett S, Oscarson S (2000) Synthesis of a d, d- and l, d-heptose-containing hexasaccharide corresponding to a structure from Haemophilus ducrey lipopolysaccharides. Tetrahedron Asymm 11:481–492

    Article  CAS  Google Scholar 

  56. Ishii K, Kubo H, Yamasaki R (2002) Synthesis of α-lactosyl-(1 → 3)-l-glycero-α-d-manno-heptopyranoside, a partial oligosaccharide structure expressed within the lipooligosaccharide produced by Neisseria gonorrhoeae strain 15253. Carbohydr Res 337:11–20

    Article  CAS  Google Scholar 

  57. Ishii K, Esumi Y, Iwasaki Y, Yamasaki R (2004) Synthesis of a 2,3-di-O-substituted heptose structure by regioselective 3-O-silylation of a 2-O-substituted heptose derivative. Eur J Org Chem 1214–1227

    Article  Google Scholar 

  58. Kubo H, Ishii K, Koshino H, Toubetto K, Naruchi K, Yamasaki R (2004) Synthesis of a 3,4-di-O-substituted heptose structure: a partial oligosaccharide expressed in neisserial lipopolysaccharide. Eur J Org Chem 1202–1213

    Article  Google Scholar 

  59. Yamasaki R, Yabe U, Kataoka C, Takeda U, Asuka S (2010) The oligosaccharides of gonococcal lipooligosaccharide contains several epitopes that are recognized by human antibodies. Infect Immun 78:3247–3257

    Article  CAS  Google Scholar 

  60. Segerstedt E, Mannerstedt K, Johansson M, Oscarson S (2004) Synthesis of the branched trisaccharide l-glycero-α-d-manno-heptopyranosyl-(1 → 3)-[β-d-glucopyranosyl-(1 → 4)]-l-glycero-α-d-manno-heptopyranose, protected to allow flexible access to Neisseria and Haemophilus LPS inner core structures. J Carbohydr Chem 23:443–452

    Article  CAS  Google Scholar 

  61. Olsson JDM, Oscarson S (2009) Synthesis of phosphorylated Neisseria meningitidis inner core lipopolysaccharide structures. Tetrahedron Asymm 20:879–886

    Article  Google Scholar 

  62. Cox AD, St Michael F, Neelamegan D, Lacelle S, Cairns C, Richards J (2010) Investigating the candidacy of LPS-based glycoconjugates to prevent invasive meningococcal disease: chemical strategies to prepare glycoconjugates with good carbohydrate loading. Glycoconj J 27:401–417

    Article  CAS  Google Scholar 

  63. Mannerstedt K, Segerstedt E, Olsson J, Oscarson S (2008) Synthesis of a common tetrasaccharide motif of Haemophilus influenzae LPS inner core structures. Org Biomol Chem 6:1087–1091

    Article  CAS  Google Scholar 

  64. Olsson JDM, Oscarson S (2010) Synthesis of phosphorylated 3,4-branched trisaccharides corresponding to LPS inner core structures of Neisseria meningitidis and Haemophilus influenzae. Carbohydr Res 345:1331–1338

    Article  CAS  Google Scholar 

  65. Ohara T, Adibekian A, Esposito D, Stallforth P, Seeberger PH (2010) Towards the synthesis of a Yersinia pestis cell wall polysaccharide: enantioselective synthesis of an l-glycero-d-manno-heptose building block. Chem Commun 46:4106–4108

    Article  CAS  Google Scholar 

  66. Paulsen H, Wulff A, Heitmann AC (1988) Synthesis of disaccharides from l-glycero-d-manno-heptose and 2-amino-2-deoxy-d-glucose. Liebigs Ann Chem 1073–1078

    Article  Google Scholar 

  67. Martin P, Lequart V, Cecchelli R, Boullanger P, Lafont D, Banoub J (2004) Novel synthesis of disaccharides containing the 2-amino-2-deoxy-β-d-glucopyranosyl unit and l-glycero-d-manno- and 7-deoxy-l-glycero-d-galacto-heptopyranoses. Chem Lett 33:696–697

    Article  CAS  Google Scholar 

  68. Antonov KV, Backinowsky LV, Grzeszcyk B, Brade L, Holst O, Zamojski A (1998) Synthesis and serological characterization of l-glycero-α-d-manno-heptopyranose-containing di- and trisaccharides of the non-reducing terminus of the Escherichia coli K-12 LPS core oligosaccharide. Carbohydr Res 314:85–93

    Article  CAS  Google Scholar 

  69. Mandal PK, Misra AK (2008) Concise synthesis of two pentasaccharides corresponding to the α-chain oligosaccharides of Neisseria gonorrhoeae and Neisseria meningitidis. Tetrahedron 64:8685–8691

    Article  CAS  Google Scholar 

  70. Yokota S, Fuji N (2007) Contributions of the lipopolysaccharide outer core oligosaccharide region on the cell surface properties of Pseudomonas aeruginosa. Comp Immunol Microbiol Infect Dis 30:97–109

    Article  Google Scholar 

  71. Komarova BS, Tsvetkov YE, Knirel YA, Zähringer U, Pier GB, Nifantiev NE (2006) Synthesis of common trisaccharide fragment of glycoforms of the outer core region of the Pseudomonas aeruginosa lipopolysaccharide. Tetrahedron Lett 47:3583–3587

    Article  CAS  Google Scholar 

  72. Komarova BS, Tsvetkov YE, Pier GB, Nifantiev NE (2008) First synthesis of pentasaccharide glycoform I of the outer core region of the Pseudomonas aeruginosa lipopolysaccharide. J Org Chem 73:8411–8421

    Article  CAS  Google Scholar 

  73. Campodónico VL, Gadjeva M, Paradis-Bleau C, Uluer A, Pier GB (2008) Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis. Trends Mol Med 14:120–133

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, A-1190, Vienna, Austria

    Paul Kosma & Alla Zamyatina

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  1. Paul Kosma
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  2. Alla Zamyatina
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Correspondence to Paul Kosma .

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Editors and Affiliations

  1. N.D. Zelinsky Institute of Organic Chemi, Russian Academy of Sciences, Leninsky Prospekt 47, Moscow, V-334, 119991, Russian Federation

    Yuriy A. Knirel

  2. Centre for Human Immunology and, Department of Microbiology and Immunolog, University of Western Ontario, London, N6A 5C1, Ontario, Canada

    Miguel A. Valvano

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Kosma, P., Zamyatina, A. (2011). Chemical Synthesis of Lipopolysaccharide Core. In: Knirel, Y., Valvano, M. (eds) Bacterial Lipopolysaccharides. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0733-1_5

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