Skip to main content

Advertisement

SpringerLink
Log in

Cationic antimicrobial peptides in clinical development, with special focus on thanatin and heliomicin

  • Review
  • Published:
European Journal of Clinical Microbiology & Infectious Diseases Aims and scope Submit manuscript

Abstract

Cationic host-defence antimicrobial peptides are recognised as an important component of the innate immune response in most multicellular organisms. In humans, several antimicrobial peptides have recently been recognised as key factors in the pathology of diseases such as cystic fibrosis, septic shock, atopic dermatitis and morbus Kostmann. To date, several hundred cationic antimicrobial peptides have been characterised. They are amphipathic peptides, comprising 20 to 50 amino acids, and exhibiting large structural diversity. These peptides display a broad spectrum of activity against bacterial, fungal and viral pathogens. Their mode of action is best known for cecropins and magainins, which act upon the cytoplasmic membrane of microorganisms, causing its disruption by a detergent-like activity and pore formation. In the last few years, several of these peptides or analogues (derived from magainin, protegrin, indolicidin and histatin) were in advanced clinical development, especially for localised infections (oral and cutaneous infections, pneumonias etc.). Several other molecules (rBPI, heliomicin and thanatin) are currently under development for various systemic infections (Staphylococcus sp., Aspergillus sp., Candida sp. etc.) and may represent important additions to the anti-infectious therapeutic arsenal.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Breithaupt H (1999) The new antibiotics. Nature 17:1165–1169

    Article  CAS  Google Scholar 

  2. Gura T (2001) Innate immunity: ancient system gets new respect. Science 291:2068–2071

    Article  PubMed  CAS  Google Scholar 

  3. Hadley EB, Hancock RE (2010) Strategies for the discovery and advancement of novel cationic antimicrobial peptides. Curr Top Med Chem 10:1872–1881

    PubMed  CAS  Google Scholar 

  4. Hoffmann JA, Kafatos FC, Janeway CA, Ezekowitz RA (1999) Phylogenetic perspectives in innate immunity. Science 284:1313–1318

    Article  PubMed  CAS  Google Scholar 

  5. Lehrer RI, Ganz T (1999) Anti-microbial peptides in mammalian and insect host defence. Curr Opin Immunol 11:23–27

    Article  PubMed  CAS  Google Scholar 

  6. Bulet P, Stocklin R, Menin L (2004) Anti-microbial peptides: from invertebrates to vertebrates. Immunol Rev 198:169–184

    Article  PubMed  CAS  Google Scholar 

  7. Hamill P, Brown K, Jenssen H, Hancock RE (2008) Novel anti-infectives: is host defence the answer? Curr Opin Biotechnol 19:628–636

    Article  PubMed  CAS  Google Scholar 

  8. Guaní-Guerra E, Santos-Mendoza T, Lugo-Reyes SO, Terán LM (2010) Antimicrobial peptides: general overview and clinical implications in human health and disease. Clin Immunol 135:1–11

    Article  PubMed  Google Scholar 

  9. Guenneugues M, Dimarcq JL (2002) Lead optimisation of heliomicin with 3D structure analysis/molecular modelling of analogues. 10th International Congress of Mycology, International Union of Microbiological Societies World Congresses —7, Paris, France

  10. Hiemstra PS (2001) Epithelial antimicrobial peptides and proteins: their role in host defence and inflammation. Paediatr Respir Rev 2:306–310

    Article  PubMed  CAS  Google Scholar 

  11. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T et al (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 347:1151–1160

    Article  PubMed  CAS  Google Scholar 

  12. Putsep K, Carlsson G, Boman HG, Andersson M (2002) Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study. Lancet 360:1144–1149

    Article  PubMed  CAS  Google Scholar 

  13. Hoffmann JA (2003) The immune response of Drosophila. Nature 426:33–38

    Article  PubMed  CAS  Google Scholar 

  14. Hetru C, Troxler L, Hoffmann JA (2003) Drosophila melanogaster antimicrobial defence. J Infect Dis 187 [Suppl 2]:S327–S334

    Article  PubMed  CAS  Google Scholar 

  15. Dimarcq JL, Bulet P, Hetru C, Hoffmann JA (1998) Cysteine-rich anti-microbial peptides in invertebrates. Biopolymers 47:465–477

    Article  PubMed  CAS  Google Scholar 

  16. Boman HG (2003) Antibacterial peptides: basic facts and emerging concepts. J Intern Med 254:197–215

    Article  PubMed  CAS  Google Scholar 

  17. Boman HG (1998) Gene-encoded peptide antibiotics and the concept of innate immunity: an update review. Scand J Immunol 48:15–25

    Article  PubMed  CAS  Google Scholar 

  18. Berkowitz BA, Bevins CL, Zasloff MA (1990) Magainins: a new family of membrane-active host defence peptides. Biochem Pharmacol 39:625–629

    Article  PubMed  CAS  Google Scholar 

  19. Lehrer RI, Ganz T (1996) Endogenous vertebrate antibiotics. Defensins, protegrins, and other cysteine-rich anti-microbial peptides. Ann N Y Acad Sci 797:228–239

    Article  PubMed  CAS  Google Scholar 

  20. Garcia-Olmedo F, Molina A, Alamillo JM, Rodriguez-Palenzuela P (1998) Plant defence peptides. Biopolymers 47:479–491

    Article  PubMed  CAS  Google Scholar 

  21. Van Abel RJ, Tang YQ, Rao VS, Dobbs CH, Tran D, Barany G (1995) Synthesis and characterization of indolicidin, a tryptophan-rich anti-microbial peptide from bovine neutrophils. Int J Pept Protein Res 45:401–409

    Article  PubMed  Google Scholar 

  22. Bulet P, Hetru C, Dimarcq JL, Hoffmann D (1999) Anti-microbial peptides in insects; structure and function. Dev Comp Immunol 23:329–344

    Article  PubMed  CAS  Google Scholar 

  23. Hancock RE, Rozek A (2002) Role of membrane in the activities of antimicrobial cationic peptides. FEMS Microbiol Lett 206:143–149

    Article  PubMed  CAS  Google Scholar 

  24. Oren Z, Shai Y (1998) Mode of action of linear amphipathic alpha-helical anti-microbial peptides. Biopolymers 47:451–463

    Article  PubMed  CAS  Google Scholar 

  25. Hwang PM, Vogel HJ (1998) Structure-function relationships of anti-microbial peptides. Biochem Cell Biol 76:235–346

    Article  PubMed  CAS  Google Scholar 

  26. Cociancich S, Ghazi A, Hetru C, Hoffmann JA, Letellier L (1993) Insect defensin, an inducible antibacterial peptide, forms voltage-dependent channels in Micrococcus luteus. J Biol Chem 268:19239–19245

    PubMed  CAS  Google Scholar 

  27. Ganz T, Lehrer RI (1999) Antibiotic peptides from higher eukaryotes: biology and applications. Mol Med Today 5:292–297

    Article  PubMed  CAS  Google Scholar 

  28. Otvos L, Rogers ME, Consolvo PJ, Condie BA, Lovas S, Bulet P (2000) Interaction between heat shock proteins and anti-microbial peptides. Biochemistry 39:14150–14159

    Article  PubMed  CAS  Google Scholar 

  29. Thevissen K, Cammue BP, Lemaire K, Winderickx J, Dickson RC, Lester RL (2000) 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

    Article  PubMed  CAS  Google Scholar 

  30. Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3:238–250

    Article  PubMed  CAS  Google Scholar 

  31. Scott MG, Rosenberger CM, Gold MR, Finlay BB, Hancock RE (2000) An alpha-helical cationic anti-microbial peptide selectively modulates macrophage responses to lipopolysaccharide and directly alters macrophage gene expression. J Immunol 165:3358–3365

    PubMed  CAS  Google Scholar 

  32. Scott MG, Hancock RE (2000) Cationic anti-microbial peptides and their multifunctional role in the immune system. Crit Rev Immunol 20:407–431

    PubMed  CAS  Google Scholar 

  33. Dimarcq JL (2003) Developing insect-derived drug candidates. Drug Discov Today 8:107–110

    Article  PubMed  Google Scholar 

  34. Michaelson D, Rayner J, Couto M, Ganz T (1992) Cationic defensins arise from charge-neutralized propeptides: mechanism for avoiding leukocyte autocytotoxicity? J Leukoc Biol 51:634–639

    PubMed  CAS  Google Scholar 

  35. Hancock REW (2000) Cationic anti-microbial peptides: toward clinical application. Expert Opin Investig Drugs 9:1723–1729

    Article  PubMed  CAS  Google Scholar 

  36. Andrès E, Dimarcq JL (2004) Peptides anti-microbiens cationiques: de l’étude de l’immunité innée à la production de médicaments. Rev Med Interne 25:629–635

    Article  PubMed  Google Scholar 

  37. Andrès E, Dimarcq JL (2004) Cationic antimicrobial peptides: update of clinical development. J Intern Med 255:519–520

    Article  PubMed  Google Scholar 

  38. O’Neil DA (2011) Prospects for peptides anti-infective agents. Innov Pharm Technol 3:62–66

    Google Scholar 

  39. Jacob L, Zasloff M (1994) Potential therapeutic applications of magainins and other anti-microbial agents of animal origin. Ciba Found Symp 186:197–216; discussion 216–223

    PubMed  CAS  Google Scholar 

  40. http://www.magainin.com Accessed July 2011

  41. Lamb HM, Wiseman LR (1998) Pexiganan acetate. Drugs 56:1047–1052

    Article  PubMed  CAS  Google Scholar 

  42. http://www.intrabiotics.com/news/index.html Accessed July 2011

  43. Loury D, Embree JR, Steinberg DA, Sonis ST, Fiddes JC (1999) Effect of local application of the anti-microbial peptide IBL-367 on the incidence and severity of oral mucositis in hamsters. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 87:544–551

    Article  PubMed  CAS  Google Scholar 

  44. Bellm L, Lehrer RI, Ganz T (2000) Protegrins: new antibiotics of mammalian origin. Expert Opin Investig Drugs 9:1731–1742

    Article  PubMed  CAS  Google Scholar 

  45. http://www.micrologixbiotech.com/index_clinical.html Accessed July 2011

  46. http://www.pharmalicencing.com Accessed July 2011

  47. Paquette DW, Simpson DM, Friden P, Braman V, Williams RC (2002) Safety and clinical effects of topical histatin gels in human with experimental gingivitis. J Clin Periodontol 29:1051–1058

    Article  PubMed  CAS  Google Scholar 

  48. Giroir BP, Quint PA, Barton P, Kirsch EA, Kitchen L, Goldstein B (1997) Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability increasing protein in children with severe meningococcal sepsis. Lancet 350:1439–1443

    Article  PubMed  CAS  Google Scholar 

  49. http://www.xoma.com Accessed July 2011

  50. Demetriades D, Smith JS, Jacobson LE, Moncure M, Minei J, Nelson BJ (1999) Bactericidal/permeability increasing protein (rBPI-21) in patients with hemorrhage due to trauma: results of a multicenter phase II clinical trial. Trauma 46:667–676

    Article  CAS  Google Scholar 

  51. Andrès E, Dimarcq JL (2007) Peptides anti-microbiens cationiques: de l’étude de l’immunité innée à la production de médicaments. Med Mal Infect 37:194–199

    Article  PubMed  Google Scholar 

  52. Lemaitre B, Reichhart JM, Hoffmann JA (1997) Drosophila host defence: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms. Proc Natl Acad Sci USA 94:14614–14619

    Article  PubMed  CAS  Google Scholar 

  53. Pages JM, Dimarcq JL, Quenin S, Hetru C (2003) Thanatin activity on multidrug resistant clinical isolates of Enterobacter aerogenes and Klebsiella pneumoniae. Int J Antimicrob Agents 22:265–269

    Article  PubMed  CAS  Google Scholar 

  54. Fehlbaum P, Bulet P, Chernysh S, Briand JP, Roussel JP, Letellier L (1996) Structure-activity analysis of thanatin, a 21-residue inducible insect defence peptide with sequence homology to frog skin antimicrobial peptides. Proc Natl Acad Sci USA 93:1221–1225

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Service de Médecine Interne, Clinique Médicale B, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

    E. Andrès

  2. Faculté de Médecine, Université de Strasbourg, Strasbourg, France

    E. Andrès

Authors
  1. E. Andrès
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Andrès.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Andrès, E. Cationic antimicrobial peptides in clinical development, with special focus on thanatin and heliomicin. Eur J Clin Microbiol Infect Dis 31, 881–888 (2012). https://doi.org/10.1007/s10096-011-1430-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10096-011-1430-8

Keywords

Search

Navigation