Alginate Oligomers and Their Use as Active Pharmaceutical Drugs

  • P. D. RyeEmail author
  • A. Tøndervik
  • H. Sletta
  • M. Pritchard
  • A. Kristiansen
  • A. Dessen
  • D. W. Thomas
Part of the Springer Series in Biomaterials Science and Engineering book series (SSBSE, volume 11)


Alginate oligomers retain most of the chemical and physical properties of the higher molecular weight commercial alginates, retaining affinity towards monovalent and divalent ions, which is dependent on the chemical composition of the oligomer. However, due to their low molecular weight, they will normally not form gels in the presence of divalent cations. This property is exploited in biological systems to chelate multivalent ions and disrupt Ca2+-mediated cross-linking. Studies have also identified interactions between alginate oligomers and complex mucin polymer systems, bacteria and extracellular polymeric substance (EPS), which suggests that these interactions are not simply the result of cationic chelation. By virtue of their low molecular weight, alginate oligomers stay in solution at high concentration without significant increase in viscosity and can be tailor-made to precisely defined chemical composition and molecular weight. This affords the opportunity to design effective formulations with precisely defined properties and biological effects. The properties now being identified for alginate oligomers represent a promising new approach in the management of chronic lung diseases, biofilm infections and antibiotic use. This chapter outlines the research performed to date, highlighting the excellent safety profile and novel chemical characteristics of alginate oligomers that emphasize their potential in multiple therapeutic applications.


Alginate oligomers Biofilms Mucus Medical device Infection control 


  1. 1.
    Bakkevig K, Sletta H, Gimmestad M, Aune R, Ertesvåg H, Degnes K, Christensen BE, Ellingsen TE, Valla S (2005) Role of the Pseudomonas fluorescens alginate lyase (AlgL) in clearing the periplasm of alginates not exported to the extracellular environment. J Bacteriol 187(24):8375–8384CrossRefGoogle Scholar
  2. 2.
    Hay ID, Rehman ZU, Moradali MF, Wang YJ, Rehm BHA (2013) Microbial alginate production, modification and its applications. Microb Biotechnol 6(6):637–650Google Scholar
  3. 3.
    Hay ID, Wang YJ, Moradali MF, Rehman ZU, Rehm BHA (2014) Genetics and regulation of bacterial alginate production. Environ Microbiol 16(10):2997–3011CrossRefGoogle Scholar
  4. 4.
    Rehm BH (2010) Bacterial polymers: biosynthesis, modifications and applications. Nat Rev Microbiol 8(8):578–592CrossRefGoogle Scholar
  5. 5.
    Robles-Price A, Wong TY, Sletta H, Valla S, Schiller NL (2004) AlgX is a periplasmic protein required for alginate biosynthesis in Pseudomonas aeruginosa. J Bacteriol 186(21):7369–7377CrossRefGoogle Scholar
  6. 6.
    Steigedal M, Sletta H, Moreno S, Mærk M, Christensen BE, Bjerkan T, Ellingsen TE, Espin G, Ertesvåg H, Valla S (2008) The Azotobacter vinelandii AlgE mannuronan C-5-epimerase family is essential for the in vivo control of alginate monomer composition and for functional cyst formation. Environ Microbiol 10(7):1760–1770CrossRefGoogle Scholar
  7. 7.
    Borgos SEF, Bordel S, Sletta H, Ertesvåg H, Jakobsen O, Bruheim P, Ellingsen TE, Nielsen J, Valla S (2013) Mapping global effects of the anti-sigma factor MucA in Pseudomonas fluorescens SBW25 through genome-scale metabolic modeling. BMC Syst Biol 7Google Scholar
  8. 8.
    Lien SK, Niedenfuhr S, Sletta H, Noh K, Bruheim P (2015) Fluxome study of Pseudomonas fluorescens reveals major reorganisation of carbon flux through central metabolic pathways in response to inactivation of the anti-sigma factor MucA. BMC Syst Biol 9Google Scholar
  9. 9.
    Lien SK, Sletta H, Ellingsen TE, Valla S, Correa E, Goodacre R, Vernstad K, Borgos SEF, Bruheim P (2013) Investigating alginate production and carbon utilization in Pseudomonas fluorescens SBW25 using mass spectrometry-based metabolic profiling. Metabolomics 9(2):403–417CrossRefGoogle Scholar
  10. 10.
    Ertesvåg H (2015) Alginate-modifying enzymes: biological roles and biotechnological uses. Front Microbiol 6:10Google Scholar
  11. 11.
    Ertesvåg H, Høidal HK, Hals IK, Rian A, Doseth B, Valla S (1995) A family of modular type mannuronan C-5 epimerase genes controls alginate structure in Azotobacter vinelandii. Mol Microbiol 16(4):719–731CrossRefGoogle Scholar
  12. 12.
    Høidal HK, Svanem BIG, Gimmestad M, Valla S (2000) Mannuronan C-5 epimerases and cellular differentiation of Azotobacter vinelandii. Environ Microbiol 2(1):27–38CrossRefGoogle Scholar
  13. 13.
    Tøndervik A, Klinkenberg G, Aachmann FL, Svanem BIG, Ertesvåg H, Ellingsen TE, Valla S, Skjåk-Bræk G, Sletta H (2013) Mannuronan C-5 epimerases suited for tailoring of specific alginate structures obtained by high-throughput screening of an epimerase mutant library. Biomacromolecules 14(8):2657–2666CrossRefGoogle Scholar
  14. 14.
    Fischl R, Bertelsen K, Gaillard F, Coelho S, Michel G, Klinger M, Boyen C, Czjzek M, Herve C (2016) The cell-wall active mannuronan C5-epimerases in the model brown alga Ectocarpus: from gene context to recombinant protein. Glycobiology 26(9):973–983CrossRefGoogle Scholar
  15. 15.
    Ye NH, Zhang XW, Miao M, Fan X, Zheng Y, Xu D, Wang JF, Zhou L, Wang DS, Gao Y, Wang YT, Shi WY, Ji PF, Li DM, Guan Z, Shao CW, Zhuang ZM, Gao ZW, Qi J, Zhao FQ (2015) Saccharina genomes provide novel insight into kelp biology. Nat Commun 6Google Scholar
  16. 16.
    Inoue A, Satoh A, Morishita M, Tokunaga Y, Miyakawa T, Tanokura M, Ojima T (2016) Functional heterologous expression and characterization of mannuronan C5-epimerase from the brown alga Saccharina japonica. Algal Res 16:282–291CrossRefGoogle Scholar
  17. 17.
    Aarstad OA, Tøndervik A, Sletta H, Skjåk-Bræk G (2012) Alginate sequencing: an analysis of block distribution in alginates using specific alginate degrading enzymes. Biomacromolecules 13(1):106–116CrossRefGoogle Scholar
  18. 18.
    Aarstad O, Strand BL, Klepp-Andersen LM, Skjåk-Bræk G (2013) Analysis of G-block distributions and their impact on gel properties of in vitro epimerized mannuronan. Biomacromolecules 14(10):3409–3416CrossRefGoogle Scholar
  19. 19.
    Haug A, Larsen B, Smidsrød O (1967) Studeis on the sequence of uronic acid residues in alginic acid. Acta Chem Scand 21:691–704CrossRefGoogle Scholar
  20. 20.
    Haug A, Larsen B, Smidsrød O (1974) Uronic acid sequence in alginate from different sources. Carbohydr Res 32:217–225CrossRefGoogle Scholar
  21. 21.
    Campa C, Oust A, Skjåk-Bræk G, Paulsen BS, Paoletti S, Christensen BE, Ballance S (2004) Determination of average degree of polymerisation and distribution of oligosaccharides in a partially acid-hydrolysed homopolysaccharide: a comparison of four experimental methods applied to mannuronan. J Chromatogr A 1026(1-2):271–281CrossRefGoogle Scholar
  22. 22.
    Padol AM, Draget KI, Stokke BT (2016) Effects of added oligoguluronate on mechanical properties of Ca – alginate – oligoguluronate hydrogels depend on chain length of the alginate. Carbohydr Polym 147:234–242CrossRefGoogle Scholar
  23. 23.
    Nordgård CT, Draget KI (2011) Oligosaccharides as modulators of rheology in complex mucous systems. Biomacromolecules 12(8):3084–3090CrossRefGoogle Scholar
  24. 24.
    Nordgård CT, Nonstad U, Olderøy MO, Espevik T, Draget KI (2014) Alterations in mucus barrier function and matrix structure induced by guluronate oligomers. Biomacromolecules 15(6):2294–2300CrossRefGoogle Scholar
  25. 25.
    Powell LC, Pritchard MF, Emanuel C, Onsøyen E, Rye PD, Wright CJ, Hill KE, Thomas DW (2014) A nanoscale characterization of the interaction of a novel alginate oligomer with the cell surface and motility of Pseudomonas aeruginosa. Am J Respir Cell Mol Biol 50(3):483–492CrossRefGoogle Scholar
  26. 26.
    Powell LC, Sowedan A, Khan S, Wright CJ, Hawkins K, Onsøyen E, Myrvold R, Hill KE, Thomas DW (2013) The effect of alginate oligosaccharides on the mechanical properties of Gram-negative biofilms. Biofouling 29(4):413–421CrossRefGoogle Scholar
  27. 27.
    Draget KI (2016) Alginates: fundamental properties and food applications. Reference module in food. Science:1–9Google Scholar
  28. 28.
    Kreda SM, Davis CW, Rose MC (2012) CFTR, mucins, and mucus obstruction in cystic fibrosis. Cold Spring Harb Perspect Med 2(9):32CrossRefGoogle Scholar
  29. 29.
    Garcia MAS, Yang N, Quinton PM (2009) Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion. J Clin Invest 119(9):2613–2622CrossRefGoogle Scholar
  30. 30.
    Gustafsson JK, Ermund A, Ambort D, Johansson MEV, Nilsson HE, Thorell K, Hebert H, Sjovall H, Hansson GC (2012) Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. J Exp Med 209(7):1263–1272CrossRefGoogle Scholar
  31. 31.
    Yang N, Garcia MA, Quinton PM (2013) Normal mucus formation requires cAMP-dependent HCO3- secretion and Ca2+-mediated mucin exocytosis. J Physiol 591(18):4581–4593CrossRefGoogle Scholar
  32. 32.
    De Lisle RC, Borowitz D (2013) The cystic fibrosis intestine. Cold Spring Harb Perspect Med 3(9)Google Scholar
  33. 33.
    Mascarenhas MR (2003) Treatment of gastrointestinal problems in cystic fibrosis. Curr Treat Options Gastroenterol 6(5):427–441CrossRefGoogle Scholar
  34. 34.
    Vitko M, Valerio DM, Rye PD, Onsøyen E, Myrset AH, Dessen A, Drumm ML, Hodges CA (2016) A novel guluronate oligomer improves intestinal transit and survival in cystic fibrosis mice. J Cyst FibrosGoogle Scholar
  35. 35.
    Ambort D, Johansson ME, Gustafsson JK, Nilsson HE, Ermund A, Johansson BR, Koeck PJ, Hebert H, Hansson GC (2012) Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. Proc Natl Acad Sci U S A 109(15):5645–5650CrossRefGoogle Scholar
  36. 36.
    Ermund A, Meiss LN, Gustafsson JK, Hansson GC (2015) Hyper-osmolarity and calcium chelation: effects on cystic fibrosis mucus. Eur J Pharmacol 764:109–117CrossRefGoogle Scholar
  37. 37.
    Braccini I, Grasso RP, Perez S (1999) Conformational and configurational features of acidic polysaccharides and their interactions with calcium ions: a molecular modeling investigation. Carbohydr Res 317(1-4):119–130CrossRefGoogle Scholar
  38. 38.
    Jørgensen TE, Sletmoen M, Draget KI, Stokke BT (2007) Influence of oligoguluronates on alginate gelation, kinetics, and polymer organization. Biomacromolecules 8(8):2388–2397CrossRefGoogle Scholar
  39. 39.
    Bowman KA, Aarstad OA, Nakamura M, Stokke BT, Skjåk-Bræk G, Round AN (2016) Single molecule investigation of the onset and minimum size of the calcium-mediated junction zone in alginate. Carbohydr Polym 148:52–60CrossRefGoogle Scholar
  40. 40.
    Ermund A, Recktenwald CV, Skjåk-Bræk G, Meiss LN, Onsøyen E, Rye PD, Dessen A, Myrset AH, Gustafsson JK, Hansson GC (2017) OligoG CF 5/20 normalizes cystic fibrosis mucus by chelating calciumGoogle Scholar
  41. 41.
    Sletmoen M, Maurstad G, Nordgård CT, Draget KI, Stokke BT (2012) Oligoguluronate induced competitive displacement of mucin-alginate interactions: relevance for mucolytic function. Soft Matter 8(32):8413–8421CrossRefGoogle Scholar
  42. 42.
    Pritchard MF, Powell LC, Menzies GE, Lewis PD, Hawkins K, Wright C, Doull I, Walsh TR, Onsøyen E, Dessen A, Myrvold R, Rye PD, Myrset AH, Stevens HN, Hodges LA, MacGregor G, Neilly JB, Hill KE, Thomas DW (2016) A new class of safe oligosaccharide polymer therapy to modify the mucus barrier of chronic respiratory disease. Mol Pharm 13(3):863–872CrossRefGoogle Scholar
  43. 43.
    Bazett M, Honeyman L, Stefanov AN, Pope CE, Hoffman LR, Haston CK (2015) Cystic fibrosis mouse model-dependent intestinal structure and gut microbiome. Mamm Genome 26(5-6):222–234CrossRefGoogle Scholar
  44. 44.
    De Lisle RC (2007) Altered transit and bacterial overgrowth in the cystic fibrosis mouse small intestine. Am J Physiol Gastrointest Liver Physiol 293(1):G104–G111CrossRefGoogle Scholar
  45. 45.
    Laxminarayan R, Duse A, Wattal C, Zaidi AKM, Wertheim HFL, Sumpradit N, Vlieghe E, Hara GL, Gould IM, Goossens H, Greko C, So AD, Bigdeli M, Tomson G, Woodhouse W, Ombaka E, Peralta AQ, Qamar FN, Mir F, Kariuki S, Bhutta ZA, Coates A, Bergstrom R, Wright GD, Brown ED, Cars O (2013) Antibiotic resistance-the need for global solutions. Lancet Infect Dis 13(12):1057–1098CrossRefGoogle Scholar
  46. 46.
    Hengzhuang W, Song Z, Ciofu O, Onsøyen E, Rye PD, Hoiby N (2016) OligoG CF-5/20 disruption of mucoid pseudomonas aeruginosa biofilm in a murine lung infection model. Antimicrob Agents Chemother 60(5):2620–2626CrossRefGoogle Scholar
  47. 47.
    Khan S, Tøndervik A, Sletta H, Klinkenberg G, Emanuel C, Onsøyen E, Myrvold R, Howe RA, Walsh TR, Hill KE, Thomas DW (2012) Overcoming drug resistance with alginate oligosaccharides able to potentiate the action of selected antibiotics. Antimicrob Agents Chemother 56(10):5134–5141CrossRefGoogle Scholar
  48. 48.
    Russo TA, Beanan JM, Olson R, MacDonald U, Luke NR, Gill SR, Campagnari AA (2008) Rat pneumonia and soft-tissue infection models for the study of Acinetobacter baumannii biology. Infect Immun 76(8):3577–3586CrossRefGoogle Scholar
  49. 49.
    Powell LC, Pritchard MF, Emanuel C, Khan S, Sletta H, Tøndervik A, Klinkenberg G, Onsøyen ER, Myrvold R, Rye P, Hill KE, Thomas DW (2013) Characterization of the effect of a novel antifungal alginate oligomer on fungal hyphae formation. Pediatr Pulmonol 48:329–329Google Scholar
  50. 50.
    Pritchard MF, Powell LC, Onsøyen E, Rye PD, Hill KE, Thomas DW (2014) Utilization of a recombinant in vitro epithelial model to study the effect of novel therapies on microbial colonization and invasion of the epidermis. Wound Repair Regen 22(5):A95Google Scholar
  51. 51.
    Tøndervik A, Sletta H, Klinkenberg G, Emanuel C, Powell LC, Pritchard MF, Khan S, Craine KM, Onsøyen E, Rye PD, Wright C, Thomas DW, Hill KE (2014) Alginate oligosaccharides inhibit fungal cell growth and potentiate the activity of antifungals against candida and aspergillus spp. PLoS One 9(11)Google Scholar
  52. 52.
    Kohler T, Curty LK, Barja F, van Delden C, Pechere JC (2000) Swarming of Pseudomonas aeruginosa is dependent on cell-to-cell signaling and requires flagella and pili. J Bacteriol 182(21):5990–5996CrossRefGoogle Scholar
  53. 53.
    Pritchard MF, Ferguson E, Powell L, Onsøyen E, Rye P, Hill K, Thomas DW (2015) Characterization of the in vitro interaction of an alginate oligosaccharide (OligoG CF-5/20) with Pseudomonal biofilms using fluorescent labelling and quantitative image analysis. Pediatr Pulmonol 50(S41):S295Google Scholar
  54. 54.
    Pritchard MF, Powell L, Jack AA, Powell K, Onsøyen E, Rye PD, Beck PD, Hill KE, Thomas DW (2016) OligoG CF-5/20 induces microcolony disruption and potentiates the activity of colistin against multidrug resistant Pseudomonal biofilms. Pediatr Pulmonol 51(S45):S285Google Scholar
  55. 55.
    Sherbrock-Cox V, Russell NJ, Gacesa P (1984) The purification and chemical characterisation of the alginate present in extracellular material produced by mucoid strains of Pseudomonas aeruginosa. Carbohydr Res 135(1):147–154CrossRefGoogle Scholar
  56. 56.
    Pritchard MF, Powell L, Khan S, Griffiths PC, Mansour OT, Schweins R, Beck K, Buurma NJ, Dempsey CE, Wright CJ, Rye PD, Hill KE, Thomas DW, Ferguson EL (2017) The antimicrobial effects of the alginate oligomer OligoG CF-5/20 are independent of direct bacterial cell membrane disruption. Sci Rep. (in press).
  57. 57.
    Jack AA, Khan S, Pritchard MF, Beck K, Onsøyen E, Rye PD, Thomas DW, Hill KE (2016) OligoG CF-5/20 modifies the Las and Rhl signalling pathways in a time dependent manner in Pseudomonas aeruginosa PAO1. Pediatr Pulmonol 51(S45):S333–S334Google Scholar
  58. 58.
    Ryall B, Carrara M, Zlosnik JE, Behrends V, Lee X, Wong Z, Lougheed KE, Williams HD (2014) The mucoid switch in Pseudomonas aeruginosa represses quorum sensing systems and leads to complex changes to stationary phase virulence factor regulation. PLoS One 9(5):e96166CrossRefGoogle Scholar
  59. 59.
    Hall S, McDermott C, Anoopkumar-Dukie S, McFarland AJ, Forbes A, Perkins AV, Davey AK, Chess-Williams R, Kiefel MJ, Arora D, Grant GD (2016) Cellular effects of pyocyanin, a secreted virulence factor of pseudomonas aeruginosa. Toxins (Basel) 8(8)Google Scholar
  60. 60.
    Chang CY, Krishnan T, Wang H, Chen Y, Yin WF, Chong YM, Tan LY, Chong TM, Chan KG (2014) Non-antibiotic quorum sensing inhibitors acting against N-acyl homoserine lactone synthase as druggable target. Sci Rep 4(4275)Google Scholar
  61. 61.
    Roberts JL, Khan S, Emanuel C, Powell LC, Pritchard MF, Onsøyen E, Myrvold R, Thomas DW, Hill KE (2013) An in vitro study of alginate oligomer therapies on oral biofilms. J Dent 41(10):892–899CrossRefGoogle Scholar
  62. 62.
    Sashwati R, Ganesh K, Miller C, Chaney S, Mann E, Elgharably H, Bergdall V, Wozniak D, Rye PD, Onsoyen E, Sen CK (2013) Prevention and disruption of multispecies biofilm formation and improved healing outcome using OligoG in a reproducible porcine burn wound model. In: Abstracts of the military health system research symposium (MHSRS), Fort Lauderdale, Florida, 12–15 Aug 2013Google Scholar
  63. 63.
    Dessen A, Rye P (2016) Use of alginate oligomers as blood anticoagulants US Patent US2016/331777 A1, 2016Google Scholar
  64. 64.
    Segal HC, Hunt BJ, Gilding K (1998) The effects of alginate and non-alginate wound dressings on blood coagulation and platelet activation. J Biomater Appl 12(3):249–257CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • P. D. Rye
    • 1
    Email author
  • A. Tøndervik
    • 2
  • H. Sletta
    • 2
  • M. Pritchard
    • 3
  • A. Kristiansen
    • 1
  • A. Dessen
    • 1
  • D. W. Thomas
    • 3
  1. 1.AlgiPharma ASSandvikaNorway
  2. 2.Department of Biotechnology and NanomedicineSINTEF Materials and ChemistryTrondheimNorway
  3. 3.Advanced Therapies GroupCardiff University School of DentistryCardiffUK

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