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Antimicrobial peptides of multicellular organisms

Nature volume 415, pages 389–395 (2002)Cite this article

Abstract

Multicellular organisms live, by and large, harmoniously with microbes. The cornea of the eye of an animal is almost always free of signs of infection. The insect flourishes without lymphocytes or antibodies. A plant seed germinates successfully in the midst of soil microbes. How is this accomplished? Both animals and plants possess potent, broad-spectrum antimicrobial peptides, which they use to fend off a wide range of microbes, including bacteria, fungi, viruses and protozoa. What sorts of molecules are they? How are they employed by animals in their defence? As our need for new antibiotics becomes more pressing, could we design anti-infective drugs based on the design principles these molecules teach us?

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Figure 1: Clustering of cationic and hydrophobic amino acids into distinct domains in several antimicrobial peptides of different structural classes.
Figure 2: The membrane target of antimicrobial peptides of multicellular organisms and the basis of specificity.
Figure 3: The Shai–Matsuzaki–Huang model of the mechanism of action of an antimicrobial peptide.
Figure 4: Signalling cascades that activate antimicrobial peptide genes in the fat body of Drosophila.

References

  1. Steiner, H., Hultmark, D., Engstrom, A., Bennich, H. & Boman, H. G. Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature 292, 246–268 (1981).

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Zasloff, M. Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proc. Natl Acad. Sci. USA 84, 5449–5453 (1987).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bechinger, B., Zasloff, M. & Opella, S. J. Structure and orientation of the antibiotic peptide magainin in membranes by solid-state nuclear magnetic resonance spectroscopy. Protein Sci. 2, 2077–2084 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Simmaco, M., Mignogna, G. & Barra, D. Antimicrobial peptides from amphibian skin: what do they tell us? Biopolymers 47, 435–450 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Romeo, D., Skerlavaj, B., Bolognesi, M. & Gennaro, R. Structure and bactericidal activity of an antibiotic dodecapeptide purified from bovine neutrophils. J. Biol. Chem. 263, 9573–9575 (1988).

    CAS  PubMed  Google Scholar 

  6. Selsted, M. E., Harwig, S. S., Ganz, T., Schilling, J. W. & Lehrer, R. I. Primary structure of three human neutrophil defensins. J. Clin. Invest. 76, 1436–1439 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Selsted, M. E. et al. Indolicidin, a novel bactericidal tridecapeptide amide from neutrophils. J. Biol. Chem. 267, 4292–4295 (1992).

    CAS  PubMed  Google Scholar 

  8. Agerberth, B. et al. Amino acid sequence of PR39. Isolation from pig intestine of a new member of the family of proline arginine rich antibacterial peptides. Eur. J. Biochem. 202, 849–854 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Bulet, P. et al. A novel inducible antibacterial peptide of Drosophila carries an O-glycosylated substitution. J. Biol. Chem. 268, 14893–14897 (1993).

    CAS  PubMed  Google Scholar 

  10. Shinnar, A. E. et al. in Peptides; Chemistry and Biology. Proc. 14th Am. Peptide Symp. (eds Kaumaya, P. & Hodges, R.) 189–191 (Mayflower Scientific, Leiden, 1996).

    Google Scholar 

  11. Tang, Y. Q. et al. A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated α-defensins. Science 286, 498–502 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Kim, H. S. et al. Pepsin mediated processing of the cytoplasmic histone 2A to the strong antimicrobial peptide Buforin I. J. Immunol. 165, 3268–3274 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Ulvatne, H. & Vorland, L. H. Bactericidal kinetics of three lactoferricins against S. aureus and E. coli. Scand. J. Infect. Dis. 33, 507–511 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Zanetti, M., Gennaro, R., Scocchi, M. & Skerlavaj, B. Structure and biology of cathelicins. Adv. Exp. Med. Biol. 479, 203–218 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Boman, H. G. Innate immunity and the normal microflora. Immunol. Rev. 173, 5–16 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Maloy, W. L. & Kari, U. P. Structure-activity studies on magainins and other host defense peptides. Biopolymers 37, 105–122 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Fernandez-Lopez, S. et al. Antibacterial agents based on the cyclic d,l-α-peptide architecture. Nature 412, 452–455 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Oren, Z. & Shai, Y. Cyclization of a cytolytic amphipathic α-helical peptide and its diastereomer: effect on structure, interaction with model membranes, and biological function. Biochemistry 39, 6103–6114 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Porter, E. A., Wang, X., Lee, H. S., Weisblum, B. & Gellman, S. H. Non-haemolytic β-amino acid oligomers. Nature 404, 565 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Hamuro, Y., Schneider, J. P. & DeGrado, W. F. De novo design of antibacterial β-peptides. J. Am. Chem. Soc. 121, 12200–12201 (1999).

    Article  CAS  Google Scholar 

  21. Matsuzaki, K. Why and how are peptide–lipid interactions utilized for self-defense? Magainins and tachyplesins as archetypes. Biochim. Biophys. Acta 1462, 1–10 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Yang, L., Weiss, T. M., Lehrer, R. I. & Huang, H. W. Crystallization of antimicrobial pores in membranes: magainin and protegrin. Biophys. J. 79, 2002–2009 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shai, Y. Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by α-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochim. Biophys. Acta 1462, 55–70 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Brotz, H. et al. Role of lipid-bound peptidoglycan precursors in the formation of pores by nisin, epidermin and other lantibiotics. Mol. Microbiol. 30, 317–327 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Thevissen, K. et al. A gene encoding a sphingolipid biosynthesis enzyme determines the sensitivity of Saccharomyces cerevisiae to an antifungal plant defensin from dahlia (Dahlia merckii). Proc. Natl Acad. Sci. USA 97, 9531–9536 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Westerhoff, H. V., Juretic, D., Hendler, R. W. & Zasloff, M. Magainins and the disruption of membrane-linked free-energy transduction. Proc. Natl Acad. Sci. USA 86, 6597–6601 (1989).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bierbaum, G. & Sahl, H.-G. Induction of autolysis of Staphylocci by the basic peptide antibiotics pep5 and nisin and their influence on the activity of autolytic enzymes. Arch. Microbiol. 141, 249–254 (1985).

    Article  CAS  PubMed  Google Scholar 

  28. Kragol, G. et al. The antibacterial peptide pyrrhocoricin inhibits the ATPase actions of DnaK and prevents chaperone-assisted protein folding. Biochemistry 40, 3016–3026 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Ge, Y. et al. In vitro antibacterial properties of pexiganan, an analog of magainin. Antimicrob. Agents Chemother. 43, 782–788 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hancock, R. E., Falla, T. & Brown, M. Cationic bactericidal peptides. Adv. Microbial Phys. 37, 135–175 (1995).

    Article  CAS  Google Scholar 

  31. Groisman, E. A. The ins and outs of virulence gene expression: Mg2+ as a regulatory signal. Bioessays 20, 96–101 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Gunn, J. S., Ryan, S. S., Van Velkinburgh, J. C., Ernst, R. K. & Miller, S. I. Genetic and functional analysis of a PmrA–PmrB-regulated locus necessary for lipopolysaccharide modification, antimicrobial peptide resistance, and oral virulence of Salmonella enterica serovar typhimurium. Infect. Immun. 68, 6139–6146 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kylsten, P., Samakovlis, C. & Hultmark, D. The cecropin locus in Drosophila: a compact gene cluster involved in response to infection. EMBO J. 9, 217–224 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Engström, Y. et al. κB like motifs regulate the induction of immune genes in Drosophila. J. Mol. Biol. 232, 327–333 (1993).

    Article  PubMed  Google Scholar 

  35. Kappler, C. et al. Insect immunity. Two 17 bp repeats nest a κB related sequence confer inducibility to the diptericin gene and bind a polypeptide in bacteria challenged Drosophila. EMBO J. 12, 1561–1568 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Imler, J. L. & Hoffmann, J. A. Toll receptors in innate immunity. Trends Cell Biol. 11, 304–311 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Stoven, S., Ando, I., Kadalayil, L., Engstrom, Y. & Hultmark, D. Activation of the Drosophila NF-κB factor relish by rapid endoproteolytic cleavage. EMBO Rep. 1, 347–352 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Michel, T., Reichhart, J.-M., Hoffmann, J. & Royet, J. Drosophila Toll is activated by Gram-positive bacteria via a circulating peptidoglycan recognition protein. Nature 414, 756–759 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  39. Diamond, G. et al. Tracheal antimicrobial peptide, a cystein-rich peptide from mammalian tracheal mucosa: peptide isolation and cloning of a cDNA. Proc. Natl Acad. Sci. USA 88, 3952–3956 (1994).

    Article  ADS  Google Scholar 

  40. Schonwetter, B. S., Stolzenberg, E. D. & Zasloff, M. Epithelial antibiotics induced at sites of inflammation. Science 267, 1645–1648 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  41. Russell, J. P., Diamond, G., Tarver, A. P., Scanlin, T. F. & Bevins, C. L. Coordinate induction of two antibiotic genes in tracheal epithelial cells exposed to the inflammatory mediators LPS and tumor necrosis factor α. Infect. Immun. 64, 1565–1568 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. O'Neil, D. A. et al. Expression and regulation of the human β-defensins HBD-1 and HBD-2 in intestinal epithelium. J. Immunol. 163, 6718–6724 (1999).

    CAS  PubMed  Google Scholar 

  43. Singh, P. K. et al. Production of β-defensins by human airway epithelia. Proc. Natl Acad. Sci. USA 95, 14961–14966 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. Harder, J. et al. Mucoid Pseudomonas aeruginosa, TNF-α, and IL-1β, but not IL-6, induce human β defensin-2 in respiratory epithelia. Am. J. Respir. Cell Mol. Biol. 22, 714–721 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Harder, J., Bartels, J., Christophers, E. & Schroder, J. M. A peptide antibiotic from human skin. Nature 387, 861 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  46. Tarver, A. P. et al. Enteric β-defensin: molecular cloning and characterization of a gene with inducible intestinal epithelial cell expression associated with Cryptosporidium parvum infection. Infect. Immun. 66, 1045–1056 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Liu, L. et al. Structure and mapping of the human β-defensin 2 gene and its expression at sites of inflammation. Gene 222, 237–244 (1998).

    CAS  PubMed  Google Scholar 

  48. Murphy, J. E., Robert, C. & Kupper, T. S. Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity. J. Invest. Dermatol. 114, 602–608 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Kimbrell, D. A. & Beutler, B. The evolution and genetics of innate immunity. Nature Rev. Genet. 2, 256–267 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Dangl, J. L. & Jones, J. D. Plant pathogens and integrated defence responses to infection. Nature 411, 826–833 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  51. Brey, P. T. et al. Role of the integument in insect immunity: epicuticular abrasion and induction of cecropin synthesis in cuticular epithelial cells. Proc. Natl Acad. Sci. USA 90, 6275–6279 (1993).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Smith, J. J., Travis, S. M., Greenberg, E. P. & Welsh, M. J. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell 85, 229–236 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Goldman, M. J. et al. Human β-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 88, 553–560 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Nizet, V. et al. An antimicrobial peptide protects mice from invasive bacterial infection. Nature 414, 454–457 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  55. Ouellette, A. J. & Bevins, C. L. Paneth cell defensins and innate immunity of the small bowel. Inflamm. Bowel Dis. 7, 43–50 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Ayabe, T. et al. Secretion of microbicidal α-defensins by intestinal Paneth cells in response to bacteria. Nature Immunol. 1, 113–118 (2000).

    Article  CAS  Google Scholar 

  57. Islam, D. et al. Down-regulation of bactericidal peptides in enteric infections: A novel immune escape mechanism with bacterial DNA as a potential regulator. Nature Med. 7, 180–185 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Wilson, C. L. et al. Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286, 113–117 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Krisanaprakornkit, S. et al. Inducible expression of human β-defensin 2 by Fusobacterium nucleatum in oral epithelial cells: multiple signaling pathways and role of commensal bacteria in innate immunity and the epithelial barrier. Infect. Immun. 68, 2907–2915 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mangoni, M. L., Miele, R., Renda, T. G., Barra, D. & Simmaco, M. The synthesis of antimicrobial peptides in the skin of Rana esculenta is stimulated by microorganisms. FASEB J. 8, 1431–1432 (2001).

    Article  Google Scholar 

  61. Chertov, O., Yang, D., Howard, O. M. & Oppenheim, J. J. Leukocyte granule proteins mobilize innate host defenses and adaptive immune responses. Immunol. Rev. 177, 68–78 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Yang, D. et al. LL-37, the neutrophil granule and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FRPL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes and T cells. J. Exp. Med. 192, 1069–1074 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zasloff, M. in From Development of Novel Antimicrobial Agents: Emerging Strategies (ed Lohner, K.) 261–270 (Horizon Scientific, Wymondham, UK, 2001).

    Google Scholar 

  64. Darveau, R. P. et al. β-lactam antibiotics potentiate Magainin 2 antimicrobial activity in vitro and in vivo. Antimicrob. Agents Chemother. 35, 1153–1159 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yasin, B. et al. Evaluation of the inactivation of infectious Herpes simplex virus by host-defense peptides. Eur. J. Clin. Microbiol. Infect. Dis. 19, 187–194 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Welling, M. M., Paulusma-Annema, A., Balter, H. S., Pauwels, E. K. & Nibbering, P. H. Technetium-99m labeled antimicrobial peptides discriminate between bacterial infections and sterile inflammations. Eur. J. Nucl. Med. 27, 292–301 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Giacometti, A., Cirioni, O., Barchiesi, F. & Scalise, G. In-vitro activity and killing effect of polycationic peptides on methicillin-resistant Staphylococcus aureus and interactions with clinically used antibiotics. Diagn. Microbiol. Infect. Dis. 38, 115–118 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Haynie, S. L., Crum, G. A. & Doele, B. A. Antimicrobial activities of amphiphilic peptides covalently bonded to a water-insoluble resin. Antimicrob. Agents Chemother. 39, 301–307 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. De Gray, G., Rajasekaran, K., Smith, F, Sanford, J & Daniell, H. Expression of an antimicrobial peptide via the chloroplast genome to control phytopathogenic bacteria and fungi. Plant Physiol. 127, 852–862 (2001).

    Article  CAS  Google Scholar 

  70. Osusky, M. et al. Transgenic plants expressing cationic peptide chimeras exhibit broad-spectrum resistance to phytopathogens. Nature Biotechnol. 18, 1162–1166 (2000).

    Article  CAS  Google Scholar 

  71. Bals, R., Weiner, D. J., Moscioni, A. D., Meegalla, R. L. & Wilson, J. M. Augmentation of innate host defense by expression of a cathelicidin antimicrobial peptide. Infect. Immun. 67, 6084–6089 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Kisich, K. O., Heifets, L., Higgins, M. & Diamond, G. Antimycobacterial agent based on mRNA encoding human β-Defensin 2 enables primary macrophages to restrict growth of Mycobacterium tuberculosis. Infect. Immun. 69, 2692–2699 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Fehlbaum, P., Rao, M., Zasloff, M. & Anderson, G. M. An essential amino acid induces epithelial β-defensin expression. Proc. Natl Acad. Sci. USA 97, 12723–12728 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  74. Birchler, T. et al. Human Toll-like receptor 2 mediates induction of the antimicrobial peptide human beta defensin 2 in response to bacterial lipoprotein. Eur. J. Immunol. 31, 3131–3137 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I thank A. Nelson for his critical reading of the manuscript. I apologize to my many colleagues whose work I have not cited, owing to constraints on the length of this review.

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  1. Michael Zasloff

    Present address: Georgetown University, Medical Center, 4000 Reservoir Road NW, Washington DC, 2007-2197, USA

  2. Michael Zasloff: Correspondence and requests for material should be addressed to the author (e-mail: maz5@georgetown.edu).

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  1. Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, 19104-6059, Pennsylvania, USA

    Michael Zasloff

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Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature 415, 389–395 (2002). https://doi.org/10.1038/415389a

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