Skip to main content

Nature-Inspired Multifunctional Host Defense Peptides with Dual Antimicrobial-Immunomodulatory Activities

  • Chapter
  • First Online:

Abstract

Naturally occurring antimicrobial peptides (AMPs) have been proposed as blueprints for the development of new antimicrobials to combat the widespread emergence of bacterial resistance. Though early work in the field has predominantly focused on their broad-spectrum antimicrobial activity, mounting evidence suggests that the immunomodulating properties of these innate defense molecules may be as critical for their development into potent therapeutic agents. In this chapter, the biological activities of both natural and synthetic multifunctional host defense peptides (HDPs) are discussed, with a focus on design strategies aimed at bestowing these molecules with superior antimicrobial and immune-regulating properties, their potential clinical applications, and challenges hampering the transition of these therapeutic agents from the benchtop to the clinic.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Steiner H, Hultmark D, Engström A, Bennich H, Boman H. Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature. 1981;292(5820):246–8.

    Article  Google Scholar 

  2. Ganz T, Selsted ME, Szklarek D, et al. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985;76(4):1427.

    Article  Google Scholar 

  3. 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 U S A. 1987;84(15):5449–53.

    Article  Google Scholar 

  4. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002;415(6870):389–95.

    Article  Google Scholar 

  5. Bowdish DM, Davidson DJ, Lau YE, Lee K, Scott MG, Hancock RE. Impact of LL-37 on anti-infective immunity. J Leukocyte Biol. 2005;77(4):451–9.

    Article  Google Scholar 

  6. Scott MG, Dullaghan E, Mookherjee N, et al. An anti-infective peptide that selectively modulates the innate immune response. Nat Biotechnol. 2007;25(4):465–72.

    Article  Google Scholar 

  7. Khara JS, Wang Y, Ke X-Y, et al. Anti-mycobacterial activities of synthetic cationic α-helical peptides and their synergism with rifampicin. Biomaterials. 2014;35(6):2032–8.

    Article  Google Scholar 

  8. Hancock RE, Sahl H-G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol. 2006;24(12):1551–7.

    Article  Google Scholar 

  9. Peschel A, Sahl H-G. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat Rev Microbiol. 2006;4(7):529–36.

    Article  Google Scholar 

  10. Travis SM, Anderson NN, Forsyth WR, et al. Bactericidal activity of mammalian cathelicidin-derived peptides. Infect Immun. 2000;68(5):2748–55.

    Article  Google Scholar 

  11. Feng X, Sambanthamoorthy K, Palys T, Paranavitana C. The human antimicrobial peptide LL-37 and its fragments possess both antimicrobial and antibiofilm activities against multidrug-resistant Acinetobacter baumannii. Peptides. 2013;49:131–7.

    Article  Google Scholar 

  12. Ogata K, Linzer B, Zuberi R, Ganz T, Lehrer R, Catanzaro A. Activity of defensins from human neutrophilic granulocytes against Mycobacterium avium-Mycobacterium intracellulare. Infect Immun. 1992;60(11):4720–5.

    Google Scholar 

  13. Sharma S, Verma I, Khuller G. Biochemical interaction of human neutrophil peptide-1 with Mycobacterium tuberculosis H37Ra. Arch Microbiol. 1999;171(5):338–42.

    Article  Google Scholar 

  14. Singh PK, Jia HP, Wiles K, et al. Production of β-defensins by human airway epithelia. Proc Natl Acad Sci U S A. 1998;95(25):14961–6.

    Article  Google Scholar 

  15. Maisetta G, Batoni G, Esin S, et al. In vitro bactericidal activity of human β-defensin 3 against multidrug-resistant nosocomial strains. Antimicrob Agents Chemother. 2006;50(2):806–9.

    Article  Google Scholar 

  16. Chen X, Niyonsaba Fß, Ushio H, et al. Synergistic effect of antibacterial agents human β-defensins, cathelicidin LL-37 and lysozyme against Staphylococcus aureus and Escherichia coli. J Dermatol Sci. 2005;40(2):123–32.

    Article  Google Scholar 

  17. Nagaoka I, Hirota S, Yomogida S, Ohwada A, Hirata M. Synergistic actions of antibacterial neutrophil defensins and cathelicidins. Inflamm Res. 2000;49(2): 73–9.

    Article  Google Scholar 

  18. Niyonsaba F, Iwabuchi K, Someya A, et al. A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology. 2002;106(1):20–6.

    Article  Google Scholar 

  19. Tjabringa GS, Ninaber DK, Drijfhout JW, Rabe KF, Hiemstra PS. Human cathelicidin LL-37 is a chemoattractant for eosinophils and neutrophils that acts via formyl-peptide receptors. Int Arch Allergy Imm. 2006;140(2):103–12.

    Article  Google Scholar 

  20. Yang D, Chen Q, Schmidt AP, et al. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med. 2000;192(7):1069–74.

    Article  Google Scholar 

  21. Yang D, Chertov O, Bykovskaia S, et al. β-Defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science. 1999;286(5439):525–8.

    Article  Google Scholar 

  22. Yang D, Chen Q, Chertov O, Oppenheim JJ. Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells. J Leukocyte Biol. 2000;68(1):9–14.

    Google Scholar 

  23. Grigat J, Soruri A, Forssmann U, Riggert J, Zwirner J. Chemoattraction of macrophages, T lymphocytes, and mast cells is evolutionarily conserved within the human α-defensin family. J Immunol. 2007;179(6):3958–65.

    Article  Google Scholar 

  24. Territo M, Ganz T, Selsted M, Lehrer R. Monocyte-chemotactic activity of defensins from human neutrophils. J Clin Invest. 1989;84(6):2017.

    Article  Google Scholar 

  25. Scott MG, Davidson DJ, Gold MR, Bowdish D, Hancock RE. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol. 2002;169(7):3883–91.

    Article  Google Scholar 

  26. Chaly YV, Paleolog E, Kolesnikova T, Tikhonov I, Petratchenko E, Voitenok N. Neutrophil α-defensin human neutrophil peptide modulates cytoline production in human monocytes and adhesion molecule expression in endothelial cells. Eur Cytokine Netw. 2000;11(2):257–66.

    Google Scholar 

  27. Niyonsaba Fß, Ushio H, Nakano N, et al. Antimicrobial peptides human β-defensins stimulate epidermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokines. J Invest Dermatol. 2006;127(3):594–604.

    Article  Google Scholar 

  28. Salunke DB, Hazra BG, Pore VS. Steroidal conjugates and their pharmacological applications. Curr Med Chem. 2006;13(7):813–47.

    Article  Google Scholar 

  29. Rozansky R, Bachrach U, Grossowicz N. Studies on the antibacterial action of spermine. J Gen Microbiol. 1954;10(1):11–6.

    Article  Google Scholar 

  30. Bucki R, Leszczyńska K, Byfield FJ, et al. Combined antibacterial and anti-inflammatory activity of a cationic disubstituted dexamethasone-spermine conjugate. Antimicrob Agents Chemother. 2010;54(6):2525–33.

    Article  Google Scholar 

  31. Wang Y, Ke X-Y, Khara JS, et al. Synthetic modifications of the immunomodulating peptide thymopentin to confer anti-mycobacterial activity. Biomaterials. 2014;35(9):3102–9.

    Article  Google Scholar 

  32. Majerle A, Kidrič J, Jerala R. Enhancement of antibacterial and lipopolysaccharide binding activities of a human lactoferrin peptide fragment by the addition of acyl chain. J Antimicrob Chemoth. 2003;51(5):1159–65.

    Article  Google Scholar 

  33. Liu Y, Xia X, Xu L, Wang Y. Design of hybrid β-hairpin peptides with enhanced cell specificity and potent anti-inflammatory activity. Biomaterials. 2013;34(1):237–50.

    Article  Google Scholar 

  34. Bhunia A, Mohanram H, Domadia PN, Torres J, Bhattacharjya S. Designed β-boomerang antiendotoxic and antimicrobial peptides: structures and activities in lipopolysaccharide. J Biol Chem. 2009;284(33):21991–2004.

    Article  Google Scholar 

  35. Mohanram H, Bhattacharjya S. Resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap. Antimicrob Agents Chemother. 2014;58(4):1987–96.

    Article  Google Scholar 

  36. Scudiero O, Galdiero S, Cantisani M, et al. Novel synthetic, salt-resistant analogs of human beta-defensins 1 and 3 endowed with enhanced antimicrobial activity. Antimicrob Agents Chemother. 2010;54(6):2312–22.

    Article  Google Scholar 

  37. Beckloff N, Laube D, Castro T, et al. Activity of an antimicrobial peptide mimetic against planktonic and biofilm cultures of oral pathogens. Antimicrob Agents Chemother. 2007;51(11):4125–32.

    Article  Google Scholar 

  38. Hua J, Scott R, Diamond G. Activity of antimicrobial peptide mimetics in the oral cavity: II. Activity against periopathogenic biofilms and anti-inflammatory activity. Mol Oral Microbiol. 2010;25(6):426–32.

    Article  Google Scholar 

  39. Leszczyńska K, Namiot D, Byfield FJ, et al. Antibacterial activity of the human host defence peptide LL-37 and selected synthetic cationic lipids against bacteria associated with oral and upper respiratory tract infections. J Antimicrob Chemoth. 2013;68(3):610–8.

    Article  Google Scholar 

  40. Murugan RN, Jacob B, Ahn M, et al. De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-Inflammatory activities. PloS One. 2013;8(11):e80025.

    Article  Google Scholar 

  41. Padhee S, Smith C, Wu H, et al. The development of antimicrobial α-AApeptides that suppress proinflammatory immune responses. Chem Bio Chem. 2014;15(5):688–94.

    Article  Google Scholar 

  42. Matsuzaki K. Control of cell selectivity of antimicrobial peptides. BBA-Biomembranes. 2009;1788(8):1687–92.

    Article  Google Scholar 

  43. Lee EK, Kim Y-C, Nan YH, Shin SY. Cell selectivity, mechanism of action and LPS-neutralizing activity of bovine myeloid antimicrobial peptide-18 (BMAP-18) and its analogs. Peptides. 2011;32(6):1123–30.

    Article  Google Scholar 

  44. Nan YH, Bang J-K, Jacob B, Park I-S, Shin SY. Prokaryotic selectivity and LPS-neutralizing activity of short antimicrobial peptides designed from the human antimicrobial peptide LL-37. Peptides. 2012;35(2):239–47.

    Article  Google Scholar 

  45. Wang G, Elliott M, Cogen AL, Ezell EL, Gallo RL, Hancock RE. Structure, dynamics, and antimicrobial and immune modulatory activities of human LL-23 and its single-residue variants mutated on the basis of homologous primate cathelicidins. Biochemistry. 2012;51(2):653–64.

    Article  Google Scholar 

  46. Park KH, Nan YH, Park Y, et al. Cell specificity, anti-inflammatory activity, and plausible bactericidal mechanism of designed Trp-rich model antimicrobial peptides. BBA-Biomembranes. 2009;1788(5):1193–203.

    Article  Google Scholar 

  47. Frecer V, Ho B, Ding J. De novo design of potent antimicrobial peptides. Antimicrob Agents Chemother. 2004;48(9):3349–57.

    Article  Google Scholar 

  48. Lee E, Kim J-K, Shin S, et al. Enantiomeric 9-mer peptide analogs of protaetiamycine with bacterial cell selectivities and anti-inflammatory activities. J Pept Sci. 2011;17(10):675–82.

    Article  Google Scholar 

  49. Wang P, Nan YH, Yang S-T, et al. Cell selectivity and anti-inflammatory activity of a Leu/Lys-rich α-helical model antimicrobial peptide and its diastereomeric peptides. Peptides. 2010;31(7):1251–61.

    Article  Google Scholar 

  50. Wei L, Wu J, Liu H, et al. A mycobacteriophage-derived trehalose-6, 6'-dimycolate-binding peptide containing both antimycobacterial and anti-inflammatory abilities. FASEB J. 2013;27(8):3067–77.

    Article  Google Scholar 

  51. Eriksson OS, Geörg M, Sjölinder H, et al. Identification of cell-penetrating peptides that are bactericidal to Neisseria meningitidis and prevent inflammatory responses upon infection. Antimicrob Agents Chemother. 2013;57(8):3704–12.

    Article  Google Scholar 

  52. Chow LN, Choi K-YG, Piyadasa H, et al. Human cathelicidin LL-37-derived peptide IG-19 confers protection in a murine model of collagen-induced arthritis. Mol Immunol. 2014;57(2):86-92.

    Article  Google Scholar 

  53. Jacob B, Park I-S, Bang J-K, Shin SY. Short KR-12 analogs designed from human cathelicidin LL-37 possessing both antimicrobial and antiendotoxic activities without mammalian cell toxicity. J Pept Sci. 2013;19(11):700–7.

    Article  Google Scholar 

  54. Ciornei CD, Sigurdardóttir T, Schmidtchen A, Bodelsson M. Antimicrobial and chemoattractant activity, lipopolysaccharide neutralization, cytotoxicity, and inhibition by serum of analogs of human cathelicidin LL-37. Antimicrob Agents Chemother. 2005;49(7):2845–50.

    Article  Google Scholar 

  55. Sigurdardottir T, Andersson P, Davoudi M, Malmsten M, Schmidtchen A, Bodelsson M. In silico identification and biological evaluation of antimicrobial peptides based on human cathelicidin LL-37. Antimicrob Agents Chemother. 2006;50(9):2983–9.

    Article  Google Scholar 

  56. McInturff JE, Wang S-J, Machleidt T, et al. Granulysin-derived peptides demonstrate antimicrobial and anti-inflammatory effects against Propionibacterium acnes. J Invest Dermatol. 2005;125(2):256–63.

    Google Scholar 

  57. Wang C-Q, Yang C-S, Yang Y, Pan F, He L-Y, Wang A-M. An apolipoprotein E mimetic peptide with activities against multidrug-resistant bacteria and immunomodulatory effects. J Pept Sci. 2013;19(12):745–50.

    Article  Google Scholar 

  58. Papareddy P, Rydengård V, Pasupuleti M, et al. Proteolysis of human thrombin generates novel host defense peptides. PLoS Pathog. 2010;6(4):e1000857.

    Article  Google Scholar 

  59. Papareddy P, Kalle M, Singh S, Mörgelin M, Schmidtchen A, Malmsten M. An antimicrobial helix A-derived peptide of heparin cofactor II blocks endotoxin responses in vivo. BBA-Biomembranes. 2014;1838(5):1225–34.

    Article  Google Scholar 

  60. Fox JL. Antimicrobial peptides stage a comeback. Nat Biotechnol. 2013;31(5):379–82.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pui Lai Rachel Ee .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Khara, J., Ee, P. (2015). Nature-Inspired Multifunctional Host Defense Peptides with Dual Antimicrobial-Immunomodulatory Activities. In: Santambrogio, L. (eds) Biomaterials in Regenerative Medicine and the Immune System. Springer, Cham. https://doi.org/10.1007/978-3-319-18045-8_6

Download citation

Publish with us

Policies and ethics