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Antimicrobial Peptides: The LPS Connection

Part of the Methods in Molecular Biology book series (MIMB,volume 618)

Abstract

An expanding body of evidence is rendering manifest that many cationic antimicrobial peptides are endowed with different properties and activities, well beyond their direct action on microbes. One of the most interesting and potentially important research avenue on the alternative use of antimicrobial peptides grounds on their affinity toward lipopolysaccharide (LPS), the endotoxin, responsible for the systemic inflammatory response syndrome (SIRS) and related, often fatal, disorders that can follow Gram-negative infections. Indeed, not only do several antimicrobial peptides, such as cathelicidins, display an ability to strongly bind LPS and break its aggregates, but they have also been demonstrated to suppress LPS-induced pro-inflammatory responses in vitro and to protect from sepsis in animal models. Although many aspects still need to be carefully evaluated – some of which are highlighted here – a mix of antimicrobial, LPS-sequestering/neutralization, and immunomodulatory features make cationic peptides, and especially synthetic or semi-synthetic amphiphilic compounds built on their scheme, attractive candidates for novel drugs to be administered in antisepsis therapies. These therapies will probably hinge either on compounds able to intervene at multiple points in the sepsis cascade or on the combination of two or more immunomodulators.

Key words

  • Antimicrobial peptides
  • synthetic peptides
  • LPS
  • endotoxin
  • binding
  • neutralization
  • sepsis
  • septic shock
  • Gram-negative

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Notes

  1. 1.

    This is just one of several existing, web-based databases dedicated to AMPs, of either natural or synthetic origin; all of them are currently linked to APD2.

References

  1. Baudouin, S. V. (Ed.) (2007) Sepsis. Springer-Verlag: New York.

    Google Scholar 

  2. Angus, D. C., Linde-Zwirble, W. T., Lidicker, J., Clermont, G., Carcillo, J., and Pinsky, M. R. (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29, 1303–1310.

    CrossRef  PubMed  CAS  Google Scholar 

  3. Burchardi, H. and Schneider, H. (2004) Economic aspects of severe sepsis: a review of intensive care unit costs, cost of illness and cost effectiveness of therapy. Pharmacoeconomics 22, 793–813.

    CrossRef  PubMed  Google Scholar 

  4. Wang, J. E., Dahle, M. K., McDonald, M., Foster, S. J., Aasen, A. O., and Thiemermann, C. (2003) Peptidoglycan and lipoteichoic acid in gram-positive bacterial sepsis: receptors, signal transduction, biological effects, and synergism. Shock 20, 402–414.

    CrossRef  PubMed  CAS  Google Scholar 

  5. Kimbrell, M. R., Warshakoon, H., Cromer, J. R., Malladi, S., Hood, J. D., Balakrishna, R., Scholdberg, T. A., and David, S. A. (2008) Comparison of the immunostimulatory and proinflammatory activities of candidate Gram-positive endotoxins, lipoteichoic acid, peptidoglycan, and lipopeptides, in murine and human cells. Immunol. Lett. 118, 132–141.

    CrossRef  PubMed  CAS  Google Scholar 

  6. Beutler, B. and Rietschel, E. Th. (2003) Innate immune sensing and its roots: the story of endotoxin. Nat. Rev. Immunol. 3, 169–176.

    CrossRef  PubMed  CAS  Google Scholar 

  7. Freudenberg, M. A., Tchaptchet, S., Keck, S., Fejer, G., Huber, M., Schültze, N., Beutler, B., and Galanos, C. (2008) Lipopolysaccharide sensing an important factor in the innate immune response to Gram-negative bacterial infections: benefits and hazards of LPS hypersensitivity. Immunobiol. 213, 193–203.

    CrossRef  CAS  Google Scholar 

  8. Beutler, B., Hoebe, K., Du, X., and Ulevitch, R. J. (2003) How we detect microbes and respond to them: the Toll-like receptors and their transducers. J. Leukoc. Biol. 74, 479–485.

    CrossRef  PubMed  CAS  Google Scholar 

  9. Raetz, R. H. and Whitfield, C. (2002) Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71, 635–700.

    CrossRef  PubMed  CAS  Google Scholar 

  10. Rosenfeld, Y. and Shai, Y. (2006) Lipopolysaccharide (endotoxin)-host defense antibacterial peptides interactions: role in bacterial resistance and prevention of sepsis. Biochim. Biophys. Acta 1758, 1513–1522.

    CrossRef  PubMed  CAS  Google Scholar 

  11. Hosac, A. M. (2002) Drotrecogin alfa (activated): the first FDA-approved treatment for severe sepsis. BUMC Proc. 15, 224–227.

    Google Scholar 

  12. Shorr, A. F., Nelson, D. R., Wyncoll, D. L. A., Reinhart, K., Brunkhorst, F., Vail, G. M., and Janes, J. (2008) Protein C: a potential biomarker in severe sepsis and a possible tool for monitoring treatment with drotrecogin alfa (activated). Crit. Care 12, R45.

    CrossRef  PubMed  Google Scholar 

  13. de Pont, A. C., Bakhtiari, K., Hutten, B. A., de Jonge, E., Vroom, M. B., Meijers, J. C., Büller, H. R., and Levi, M. (2005) Recombinant human activated protein C resets thrombin generation in patients with severe sepsis – a case control study. Crit. Care 9, R490–R497.

    CrossRef  PubMed  Google Scholar 

  14. Russell, J. A. (2006) Management of sepsis. N. Engl. J. Med. 355, 1699–1713.

    CrossRef  PubMed  CAS  Google Scholar 

  15. Claessens, Y.-E. and Dhainaut, J.-F. (2007) Diagnosis and treatment of severe sepsis. Crit. Care 11(Suppl. 5), S2.

    CrossRef  PubMed  Google Scholar 

  16. Roger, T., Froidevaux, C., Le Roy, D., Reymond, M. K., Chanson, A.-L., Mauri, D., Kim Burns, K., Riederer, B. M., Akira, S., and Calandra, T. (2009) Protection from lethal Gram-negative bacterial sepsis by targeting Toll-like receptor 4. Proc. Natl. Acad. Sci. USA 106, 2348–2352.

    CrossRef  PubMed  CAS  Google Scholar 

  17. Venkataraman, R., Subramanian, S., and Kellum, J. A. (2003) Clinical review: extracorporeal blood purification in severe sepsis. Crit. Care 7, 139–145.

    CrossRef  PubMed  Google Scholar 

  18. Nalesso, F. (2005) Plasma filtration adsorption dialysis (PFAD): a new technology for blood purification. Int. J. Artif. Organs 28, 731–738.

    PubMed  CAS  Google Scholar 

  19. Nagy, G. and Pál, T. (2008) Lipopolysaccharide: a tool and target in enterobacterial vaccine development. Biol. Chem. 389, 513–520.

    CrossRef  PubMed  CAS  Google Scholar 

  20. Hancock, R. E. W. (2001) Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infect. Dis. 1, 156–164.

    CrossRef  PubMed  CAS  Google Scholar 

  21. Chapple, D. S., Hussain, R., Joannou, C. L., Hancock, R. E. W., Odell, E., Evans, R. W., and Siligardi, G. (2004) Structure and association of human lactoferrin peptides with Escherichia coli lipopolysaccharide. Antimicrob. Agents Chemother. 48, 2190–2198.

    CrossRef  PubMed  CAS  Google Scholar 

  22. Papo, N. and Shai, Y. (2005) A molecular mechanism for lipopolysaccharide protection of Gram-negative bacteria from antimicrobial peptides. J. Biol. Chem. 280, 10378–10387.

    CrossRef  PubMed  CAS  Google Scholar 

  23. Rosenfeld, Y., Sahl, H.-G., and Shai, Y. (2008) Parameters involved in antimicrobial and endotoxin detoxification activities of antimicrobial peptides. Biochemistry 47, 6468–6478.

    CrossRef  PubMed  CAS  Google Scholar 

  24. Giacometti, A., Cirioni, O., Ghiselli, R., Mocchegiani, F., Orlando, F., Silvestri, C., Bozzi, A., Di Giulio, A., Luzi, C., Mangoni, M. L., Barra, D., Saba, V., Scalise, G., and Rinaldi, A. C. (2006) Interaction of temporin L with lipopolysaccharide in vitro and in experimental rat models of septic shock caused by Gram-negative bacteria. Antimicrob. Agents Chemother. 50, 2478–2486.

    CrossRef  PubMed  CAS  Google Scholar 

  25. Wood, S. J., Miller, K. A., and David, S. A. (2004) Anti-endotoxin agents. 1. Development of fluorescent probe displacement method optimized for the rapid identification of lipopolysaccharide-binding agents. Combin. Chem. High Throughput Screen. 7, 239–249.

    CrossRef  CAS  Google Scholar 

  26. Ding, J. L., Li, P., and Ho, B. (2008) The Sushi peptides: structural characterization and mode of action against Gram-negative bacteria. Cell. Mol. Life Sci. 65, 1202–1219.

    CrossRef  PubMed  CAS  Google Scholar 

  27. Tan, N. S., Ng, M. L., Yau, Y. H., Chong, P. K., Ho, B., and Ding, J. L. (2000) Definition of endotoxin binding sites in horseshoe crab factor C recombinant sushi proteins and neutralization of endotoxin by sushi peptides. FASEB J. 14, 1801–1813.

    CrossRef  PubMed  CAS  Google Scholar 

  28. Li, P., Wohland, T., Ho, B., and Ding, J. L. (2004) Perturbation of lipopolysaccharide (LPS) micelles by Sushi 3 (S3) antimicrobial peptide. The importance of an intermolecular disulfide bond in S3 dimer for binding, disruption, and neutralization of LPS. J. Biol. Chem. 279, 50150–50156.

    CrossRef  PubMed  CAS  Google Scholar 

  29. Li, P., Sun, M., Wohland, T., Yang, D., Ho, B., and Ding, J. L. (2006) The molecular mechanisms that govern the specificity of Sushi peptides for gram negative bacterial membrane lipids. Biochemistry 45, 10554–10562.

    CrossRef  PubMed  CAS  Google Scholar 

  30. Andrä, J., Hammer, M. U., Grötzinger, J., Jakovkin, I., Lindner, B., Vollmer, E., Fedders, H., Leippe, M., and Gutsmann, T. (2009) Significance of the cyclic structure and of arginine residues for the antibacterial activity of arenicin-1 and its interaction with phospholipid and lipopolysaccharide model membranes. Biol. Chem. 390, 337–349.

    CrossRef  PubMed  Google Scholar 

  31. Andrä, J., Böhling, A., Gronewold, T. M., Schlecht, U., Perpeet, M., and Gutsmann, T. (2008) Surface acoustic wave biosensor as a tool to study the interaction of antimicrobial peptides with phospholipid and lipopolysaccharide model membranes. Langmuir 24, 9148–9153.

    CrossRef  PubMed  Google Scholar 

  32. Jerala, R. and Porro, M. (2004) Endotoxin neutralizing peptides. Curr. Top. Med. Chem. 4, 1173–1184.

    CrossRef  PubMed  CAS  Google Scholar 

  33. Andrä, J., Gutsmann, T., Garidel, P., and Brandenburg, K. (2006) Mechanisms of endotoxin neutralization by synthetic cationic compounds. J. Endotoxin Res. 12, 261–277.

    PubMed  Google Scholar 

  34. Rosenfeld, Y., Papo, N., and Shai, Y. (2006) Endotoxin (lipopolysaccharide) neutralization by innate immunity host-defense peptides: peptide properties and plausible modes of action. J. Biol. Chem. 281, 1636–1643.

    CrossRef  PubMed  CAS  Google Scholar 

  35. Shibusawa, K., Murakami, T., Yomogida, S., Tamura, H., and Nagaoka, I. (2009) Antimicrobial cathelicidin peptide CAP11 suppresses HMGB1 release from lipopolysaccharide-stimulated mononuclear phagocytes via the prevention of necrotic cell death. Intern. J. Mol. Med. 23, 341–346.

    CAS  Google Scholar 

  36. Nagaoka, I., Hirota, S., Niyonsaba, F., Hirata, M., Adachi, Y., Tamura, H., and Heumann, D. (2001) Cathelicidin family of antibacterial peptides CAP18 and CAP11 inhibit the expression of TNF-α by blocking the binding of LPS to CD14(+) cells. J. Immunol. 167, 3329–3338.

    PubMed  CAS  Google Scholar 

  37. Mookherjee, N., Rehaume, L. M., and Hancock, R. E. (2007) Cathelicidins and functional analogues as antisepsis molecules. Expert Opin. Ther. Targets 11, 993–1004.

    CrossRef  PubMed  CAS  Google Scholar 

  38. Lin, Q. P., Zhou, L. F., Li, N. N., Chen, Y. Q., Li, B. C., Cai, Y. F., and Zhang, S. Q. (2008) Lipopolysaccharide neutralization by the antibacterial peptide CM4. Eur. J. Pharmacol. 596, 160–165.

    CrossRef  PubMed  CAS  Google Scholar 

  39. Mangoni, M. L., Epand, R. F., Rosenfeld, Y., Peleg, A., Barra, D., Epand, R. M., and Shai, Y. (2008) Lipopolysaccharide, a key molecule involved in the synergism between temporins in inhibiting bacterial growth and in endotoxin neutralization. J. Biol. Chem. 283, 22907–22917.

    CrossRef  PubMed  CAS  Google Scholar 

  40. Rinaldi, A. C. (2002) Antimicrobial peptides from amphibian skin: an expanding scenario. Curr. Opin. Chem. Biol. 6, 799–804.

    CrossRef  PubMed  CAS  Google Scholar 

  41. Rosenfeld, Y., Barra, D., Simmaco, M., Shai, Y., and Mangoni, M. L. (2006b) A synergism between temporins toward Gram-negative bacteria overcomes resistance imposed by the lipopolysaccharide protective layer. J. Biol. Chem. 281, 28565–28574.

    CrossRef  PubMed  CAS  Google Scholar 

  42. Madhani, M., Barchowsky, A., Klei, L., Ross, C. R., Jackson, S. K., Harold, M., Swartz, H. M., and James, P. E. (2002) Antibacterial peptide PR-39 affects local nitric oxide and preserves tissue oxygenation in the liver during septic shock. Biochim. Biophys. Acta 1588, 232–240.

    CrossRef  PubMed  CAS  Google Scholar 

  43. Torossian, A., Gurschi, E., Bals, R., Vassiliou, T., Wulf, H. F., and Bauhofer, A. (2007) Effects of the antimicrobial peptide LL-37 and hyperthermic preconditioning in septic rats. Anesthesiology 107, 437–441.

    CrossRef  PubMed  CAS  Google Scholar 

  44. Cohen, J. (1999) Adjunctive therapy in sepsis: a critical analysis of the clinical trial programme. Br. Med. Bull. 55, 212–225.

    CrossRef  PubMed  CAS  Google Scholar 

  45. Datamonitor (2006) Stakeholder Opinions: Sepsis. Under Reaction to An Overreaction. Datamonitor: London.

    Google Scholar 

  46. Bucklin, S. E., Lake, P., Lögdberg, L., and Morrison, D. C. (1995) Therapeutic efficacy of a polymyxin B-dextran 70 conjugate in experimental model of endotoxemia. Antimicrob. Agents Chemother. 39, 1462–1466.

    CrossRef  PubMed  CAS  Google Scholar 

  47. Fuchs, P. C., Barry, A. L., and Brown, S. D. (1998) PMX-622 (polymyxin B-dextran 70) does not alter in vitro activities of 11 antimicrobial agents. Antimicrob. Agents Chemother. 42, 2765–2767.

    PubMed  CAS  Google Scholar 

  48. Lake, P., DeLeo, J., Cerasoli, F., Logdberg, L., Weetall, M., and Handley, D. (2004) Pharmacodynamic evaluation of the neutralization of endotoxin by PMX622 in mice. Antimicrob. Agents Chemother. 48, 2987–2992.

    CrossRef  PubMed  CAS  Google Scholar 

  49. Rittirsch, D., Hoesel, L. M., and Ward, P. A. (2007) The disconnect between animal models of sepsis and human sepsis. J. Leukoc. Biol. 81, 137–143.

    CrossRef  PubMed  CAS  Google Scholar 

  50. Wang, G., Li, X., and Wang, Z. (2009) APD2: the updated antimicrobial peptide database and its application in peptide design. Nucleic Acids Res. 37(database issue), D933–D937.

    CrossRef  PubMed  CAS  Google Scholar 

  51. Taylor, A. H., Heavner, G., Nedelman, M., Sherris, D., Brunt, E., Knight, D., and Ghrayeb, J. (1995) Lipopolysaccharide (LPS) neutralizing peptides reveal a lipid A binding site of LPS binding protein. J. Biol. Chem. 270, 17934–17938.

    CrossRef  PubMed  CAS  Google Scholar 

  52. Battafaraono, R. J., Dahlberg, P. S., Ratz, C. A., Johnston, J. W., Gray, B. H., Haseman, J. R., Mayo, K. H., and Dunn, D. L. (1995) Peptide derivatives of three distinct lipopolysaccharide binding proteins inhibit lipopolysaccharide-induced tumor necrosis factor-alpha secretion in vitro. Surgery 118, 318–324.

    CrossRef  PubMed  CAS  Google Scholar 

  53. Giuliani, A., Pirri, G., Bozzi, A., Di Giulio, A., Aschi, M., and Rinaldi, A. C. (2008) Antimicrobial peptides: natural templates for synthetic membrane-active compounds. Cell. Mol. Life Sci. 65, 2450–2460.

    CrossRef  PubMed  CAS  Google Scholar 

  54. Pirri, G., Giuliani, A., Nicoletto, F. S., Pizzuto, L., and Rinaldi, A. C. (2009) Lipopeptides as antiinfectives: a practical perspective. CEJB 4, 258–273.

    CAS  Google Scholar 

  55. Wu, W., Sil, D., Szostak, M. L., Malladi, S. S., Warshakoon, H. J., Kimbrell, M. R., Cromer, J. R., and David, S. A. (2009) Structure–activity relationships of lipopolysaccharide sequestration in guanylhydrazone-bearing lipopolyamines. Bioorg. Med. Chem. 17, 709–715.

    CrossRef  PubMed  CAS  Google Scholar 

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Giuliani, A., Pirri, G., Rinaldi, A.C. (2010). Antimicrobial Peptides: The LPS Connection. In: Giuliani, A., Rinaldi, A. (eds) Antimicrobial Peptides. Methods in Molecular Biology, vol 618. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-594-1_10

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  • DOI: https://doi.org/10.1007/978-1-60761-594-1_10

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