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Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies

Abstract

Short cationic amphiphilic peptides with antimicrobial and/or immunomodulatory activities are present in virtually every life form, as an important component of (innate) immune defenses. These host-defense peptides provide a template for two separate classes of antimicrobial drugs. Direct-acting antimicrobial host-defense peptides can be rapid-acting and potent, and possess an unusually broad spectrum of activity; consequently, they have prospects as new antibiotics, although clinical trials to date have shown efficacy only as topical agents. But for these compounds to fulfill their therapeutic promise and overcome clinical setbacks, further work is needed to understand their mechanisms of action and reduce the potential for unwanted toxicity, to make them more resistant to protease degradation and improve serum half-life, as well as to devise means of manufacturing them on a large scale in a consistent and cost-effective manner. In contrast, the role of cationic host-defense peptides in modulating the innate immune response and boosting infection-resolving immunity while dampening potentially harmful pro-inflammatory (septic) responses gives these peptides the potential to become an entirely new therapeutic approach against bacterial infections.

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Figure 1: Biological roles of host defense peptide.
Figure 2

References

  1. 1

    Hancock, R.E.W. & Lehrer, R. Cationic peptides: a new source of antibiotics. Trends Biotechnol. 16, 82–88 (1998).

    CAS  Article  Google Scholar 

  2. 2

    Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature 415, 389–395 (2002).

    CAS  Article  Google Scholar 

  3. 3

    Oppenheim, J.J. & Yang, D. Alarmins: chemotactic activators of immune responses. Curr. Opin. Immunol. 17, 359–365 (2005).

    CAS  Article  Google Scholar 

  4. 4

    Bowdish, D.M.E., Davidson, D.J. & Hancock, R.E.W. A re-evaluation of the role of host defense peptides in mammalian immunity. Curr. Protein Pept. Sci. 6, 35–51 (2005).

    CAS  Article  Google Scholar 

  5. 5

    http://www.bbcm.univ.trieste.it/tossi/amsdb.html

  6. 6

    Emes, R.D., Goodstadt, L., Winter, E.E. & Ponting, C.P. Comparison of the genomes of human and mouse lays the foundation of genome zoology. Hum. Mol. Genet. 12, 701–709 (2003).

    CAS  Article  Google Scholar 

  7. 7

    Patil, A., Hughes, A.L. & Zhang, G. Rapid evolution and diversification of mammalian alpha-defensins as revealed by comparative analysis of rodent and primate genes. Physiol. Genomics 20, 1–11 (2004).

    CAS  Article  Google Scholar 

  8. 8

    Crovella, S. et al. Primate beta-defensins - structure, function and evolution. Curr. Protein Pept. Sci. 6, 7–21 (2005).

    CAS  Article  Google Scholar 

  9. 9

    Peschel, A. & Sahl, H.G. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat. Rev. Microbiol. 4, 529–536 (2006).

    CAS  Article  Google Scholar 

  10. 10

    Yount, N.Y. & Yeaman M.R. Structural congruence among membrane-active host defense polypeptides of diverse phylogeny. Biochim. Biophys. Acta 9, 1373–1386 (2006).

    Article  Google Scholar 

  11. 11

    McAuliffe, O., Ross, R.P. & Hill, C. Lantibiotics: structure, biosynthesis and mode of action. FEMS Microbiol. Rev. 25, 285–308 (2001).

    CAS  Article  Google Scholar 

  12. 12

    Hsu, S.T. et al. The nisin-lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics. Nat. Struct. Mol. Biol. 11, 963–967 (2004).

    CAS  Article  Google Scholar 

  13. 13

    Finking, R. & Marahiel, M.A. Biosynthesis of nonribosomal peptides. Annu. Rev. Microbiol. 58, 453–488 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Coulter, S.N. et al. Staphylococcus aureus genetic loci impacting growth and survival in multiple infection environments. Mol. Microbiol. 30, 393–404 (1998).

    CAS  Article  Google Scholar 

  15. 15

    Jenssen, H., Hamill, P. & Hancock, R.E.W. Peptide antimicrobial agents. Clin. Microbiol. Rev. 19, 491–511 (2006).

    CAS  Article  Google Scholar 

  16. 16

    Yeaman, M.R. & Yount, N.Y. Mechanisms of antimicrobial peptide action and resistance. Pharmacol. Rev. 55, 27–55 (2003).

    CAS  Article  Google Scholar 

  17. 17

    Sahl, H.G. et al. Mammalian defensins: structures and mechanism of antibiotic activity. J. Leukoc. Biol. 77, 466–475 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Brazas, M.D. & Hancock, R.E.W. Using microarray gene signatures to elucidate mechanisms of antibiotic action and resistance. Drug Discov. Today 10, 1245–1252 (2005).

    CAS  Article  Google Scholar 

  19. 19

    Perron, G.G., Zasloff, M. & Bell, G. Experimental evolution of resistance to an antimicrobial peptide. Proc. Biol. Sci. 273, 251–256 (2006).

    CAS  Article  Google Scholar 

  20. 20

    Samuelsen, O. et al. Induced resistance to the antimicrobial peptide lactoferricin B in Staphylococcus aureus. FEBS Lett. 579, 3421–3426 (2005).

    CAS  Article  Google Scholar 

  21. 21

    Breukink, E. & de Kruijff, B. Lipid II as a target for antibiotics. Nat. Rev. Drug Discov. 5, 321–332 (2006).

    CAS  Article  Google Scholar 

  22. 22

    Zhang, L. & Falla, T.J. Antimicrobial peptides: therapeutic potential. Expert Opin. Pharmacother. 7, 653–663 (2006).

    CAS  Article  Google Scholar 

  23. 23

    Lau, Y.E. et al. Interaction and cellular localization of the human host defense peptide, LL-37, with lung epithelial cells. Infect. Immun. 73, 583–591 (2005).

    CAS  Article  Google Scholar 

  24. 24

    Sandgren, S. et al. The human antimicrobial peptide LL-37 transfers extracellular DNA plasmid to the nuclear compartment of mammalian cells via lipid rafts and proteoglycan-dependent endocytosis. J. Biol. Chem. 279, 17951–17956 (2004).

    CAS  Article  Google Scholar 

  25. 25

    McPhee, J.B., Scott, M.G. & Hancock, R.E.W. Design of host defence peptides for antimicrobial and immunity enhancing activities. Comb. Chem. High Throughput Screen. 8, 257–272 (2005).

    CAS  Article  Google Scholar 

  26. 26

    Mygind, P.H. et al. Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. Nature 437, 975–980 (2005).

    CAS  Article  Google Scholar 

  27. 27

    Cotter, P.D., Hill, C. & Ross, R.P. Bacteriocins: developing innate immunity for food. Nat. Rev. Microbiol. 3, 777–788 (2005).

    CAS  Article  Google Scholar 

  28. 28

    Hilpert, K., Volkmer-Engert, R., Walter, T. & Hancock, R.E.W. High-throughput generation of small antibacterial peptides with improved activity. Nat. Biotechnol. 23, 1008–1012 (2005).

    CAS  Article  Google Scholar 

  29. 29

    Blondelle, S.E. & Houghten, R.A. Novel antimicrobial compounds identified using synthetic combinatorial library technology. Trends Biotechnol. 14, 60–65 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Freidinger, R.M. et al. Design and synthesis of novel bioactive peptides and peptidomimetics. J. Med. Chem. 46, 5553–5566 (2003).

    CAS  Article  Google Scholar 

  31. 31

    Masip, I., Perez-Paya, E. & Messeguer, A. Peptoids as source of compounds eliciting antibacterial activity. Comb. Chem. High Throughput Screen. 8, 235–239 (2005).

    CAS  Article  Google Scholar 

  32. 32

    Robinson, J.A. et al. Properties and structure-activity studies of cyclic beta-hairpin peptidomimetics based on the cationic antimicrobial peptide protegrin I. Bioorg. Med. Chem. 13, 2055–2064 (2005).

    CAS  Article  Google Scholar 

  33. 33

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

    CAS  Article  Google Scholar 

  34. 34

    Marshall, N.J., Andruszkiewicz, R., Gupta, S., Milewski, S. & Payne, J.W. Structure-activity relationships for a series of peptidomimetic antimicrobial prodrugs containing glutamine analogues. J. Antimicrob. Chemother. 51, 821–831 (2003).

    CAS  Article  Google Scholar 

  35. 35

    Xie, L. et al. Lacticin 481: in vitro reconstitution of lantibiotic synthetase activity. Science 303, 679–681 (2004).

    CAS  Article  Google Scholar 

  36. 36

    Rink, R., et al. Lantibiotic structures as guidelines for the design of peptides that can be modified by lantibiotic enzymes. Biochem. 44, 8873–8882 (2005).

    CAS  Article  Google Scholar 

  37. 37

    Finlay, B.B. & Hancock, R.E.W. Can innate immunity be enhanced to treat infections? Nat. Rev. Microbiol. 2, 497–504 (2004).

    CAS  Article  Google Scholar 

  38. 38

    O'Neill, L.A. How Toll-like receptors signal: what we know and what we don't know. Curr. Opin. Immunol. 18, 3–9 (2006).

    CAS  Article  Google Scholar 

  39. 39

    Bowdish, D.M.E. et al. Impact of LL-37 on anti-infective immunity. J. Leukoc. Biol. 77, 451–459 (2005).

    CAS  Article  Google Scholar 

  40. 40

    Zhang, L. et al. Antimicrobial peptide therapeutics for cystic fibrosis. Antimicrob. Agents Chemother. 49, 2921–2927 (2005).

    CAS  Article  Google Scholar 

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Acknowledgements

We gratefully acknowledge financial support (to R.E.W.H.) for peptide research from the Advanced Food and Materials Network, the Canadian Institutes for Health Research (CIHR), from Genome BC and Genome Prairie for the Pathogenomics of Innate Immunity research program, and from the Foundation for the National Institutes of Health, USA, and CIHR through the Grand Challenges in Global Health Initiative, and (to H.G.S.) from the German Research Foundation (DFG, various projects), the European Community (two 5th and 6th framework projects) and the BONFOR research program of the University of Bonn. R.E.W.H. is the recipient of a Canada Research Chair.

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Correspondence to Robert E W Hancock.

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R.E.W.H. is a scientific advisory board member of Helix Biomedix and minor shareholder of Migenix, Inc., which are developing antimicrobial peptides, and a scientific advisory board member of Inimex Pharmaceuticals, which is developing immunomodulatory peptides as human therapeutics.

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Hancock, R., Sahl, HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 24, 1551–1557 (2006). https://doi.org/10.1038/nbt1267

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