The Journal of Membrane Biology

, Volume 239, Issue 1–2, pp 27–34 | Cite as

Antimicrobial Peptides: Successes, Challenges and Unanswered Questions

Article

Abstract

Multidrug antibiotic resistance is an increasingly serious public health problem worldwide. Thus, there is a significant and urgent need for the development of new classes of antibiotics that do not induce resistance. To develop such antimicrobial compounds, we must look toward agents with novel mechanisms of action. Membrane-permeabilizing antimicrobial peptides (AMPs) are good candidates because they act without high specificity toward a protein target, which reduces the likelihood of induced resistance. Understanding the mechanism of membrane permeabilization is crucial for the development of AMPs into useful antimicrobial agents. Various models, some phenomenological and others more quantitative or semimolecular, have been proposed to explain the action of AMPs. While these models explain many aspects of AMP action, none of the models captures all of the experimental observations, and significant questions remain unanswered. Here, we discuss the state of the field and pose some questions that, if answered, could speed the discovery of clinically useful peptide antibiotics.

Keywords

Antimicrobial peptide Carpet model Bacteria Permeabilization 

References

  1. Almeida PF, Pokorny A (2009) Mechanisms of antimicrobial, cytolytic, and cell-penetrating peptides: from kinetics to thermodynamics. Biochemistry 48:8083–8093CrossRefPubMedGoogle Scholar
  2. Arias CA, Murray BE (2009) Antibiotic-resistant bugs in the 21st century—a clinical super-challenge. N Engl J Med 360:439–443CrossRefPubMedGoogle Scholar
  3. Bechinger B (2009) Rationalizing the membrane interactions of cationic amphipathic antimicrobial peptides by their molecular shape. Curr Opin Colloid Interface Sci 14:349–355CrossRefGoogle Scholar
  4. Bechinger B, Lohner K (2006) Detergent-like actions of linear amphipathic cationic antimicrobial peptides. Biochim Biophys Acta 1758:1529–1539CrossRefPubMedGoogle Scholar
  5. Brahmachary M et al (2004) ANTIMIC: a database of antimicrobial sequences. Nucleic Acids Res 32(database issue D586-9):D586–D589CrossRefPubMedGoogle Scholar
  6. Cudic M, Otvos L Jr (2002) Intracellular targets of antibacterial peptides. Curr Drug Targets 3:101–106CrossRefPubMedGoogle Scholar
  7. Demegen Pharmaceuticals (2010) Pharmaceutical products. Product profiles. Novel candidiasis therapy. www.demegen.com/pharma/candidiasis.htm
  8. Easton DM et al (2009) Potential of immunomodulatory host defense peptides as novel anti-infectives. Trends Biotechnol 27:582–590CrossRefPubMedGoogle Scholar
  9. Epand RM, Epand RF (2009) Lipid domains in bacterial membranes and the action of antimicrobial agents. Biochim Biophys Acta 1788:289–294CrossRefPubMedGoogle Scholar
  10. Epand RF et al (2010) Probing the “charge cluster mechanism” in amphipathic helical cationic antimicrobial peptides. Biochemistry 49:4076–4084CrossRefPubMedGoogle Scholar
  11. Fjell CD, Hancock RE, Cherkasov A (2007) AMPer: a database and an automated discovery tool for antimicrobial peptides. Bioinformatics 23:1148–1155CrossRefPubMedGoogle Scholar
  12. Gardy JL et al (2009) Enabling a systems biology approach to immunology: focus on innate immunity. Trends Immunol 30:249–262CrossRefPubMedGoogle Scholar
  13. Gazit E et al (1996) Structure and orientation of the mammalian antibacterial peptide cecropin P1 within phospholipid membranes. J Mol Biol 258:860–870CrossRefPubMedGoogle Scholar
  14. Gregory SM et al (2008) A quantitative model for the all-or-none permeabilization of phospholipid vesicles by the antimicrobial peptide cecropin A. Biophys J 94:1667–1680CrossRefPubMedGoogle Scholar
  15. Gregory SM, Pokorny A, Almeida PF (2009) Magainin 2 revisited: a test of the quantitative model for the all-or-none permeabilization of phospholipid vesicles. Biophys J 96:116–131CrossRefPubMedGoogle Scholar
  16. Hamill P et al (2008) Novel anti-infectives: is host defence the answer? Curr Opin Biotechnol 19:628–636CrossRefPubMedGoogle Scholar
  17. Hancock RE, Sahl HG (2006) Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 24:1551–1557CrossRefPubMedGoogle Scholar
  18. He K et al (1996) Mechanism of alamethicin insertion into lipid bilayers. Biophys J 71:2669–2679CrossRefPubMedGoogle Scholar
  19. Hong RW et al (2003) Transcriptional profile of the Escherichia coli response to the antimicrobial insect peptide cecropin A. Antimicrob Agents Chemother 47:1–6CrossRefPubMedGoogle Scholar
  20. Hristova K, Selsted ME, White SH (1997) Critical role of lipid composition in membrane permeabilization by rabbit neutrophil defensins. J Biol Chem 272:24224–24233CrossRefPubMedGoogle Scholar
  21. Huang HW, Chen FY, Lee MT (2004) Molecular mechanism of peptide-induced pores in membranes. Phys Rev Lett 92:198304CrossRefPubMedGoogle Scholar
  22. Kazemzadeh-Narbat M et al (2010) Antimicrobial peptides on calcium phosphate-coated titanium for the prevention of implant-associated infections. Biomaterials 31:9519–9526CrossRefPubMedGoogle Scholar
  23. Klein E, Smith DL, Laxminarayan R (2007) Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 1999–2005. Emerg Infect Dis 13:1840–1846PubMedGoogle Scholar
  24. Ladokhin AS, Selsted ME, White SH (1997) Sizing membrane pores in lipid vesicles by leakage of co-encapsulated markers: pore formation by melittin. Biophys J 72:1762–1766CrossRefPubMedGoogle Scholar
  25. Ludtke SJ et al (1996) Membrane pores induced by magainin. Biochemistry 35:13723–13728CrossRefPubMedGoogle Scholar
  26. Matsuzaki K, Yoneyama S, Miyajima K (1997) Pore formation and translocation of melittin. Biophys J 73:831–838CrossRefPubMedGoogle Scholar
  27. Melo MN, Dugourd D, Castanho MA (2006) Omiganan pentahydrochloride in the front line of clinical applications of antimicrobial peptides. Recent Pat Antiinfect Drug Discov 1:201–207CrossRefPubMedGoogle Scholar
  28. Merrifield RB, Vizioli LD, Boman HG (1982) Synthesis of the antibacterial peptide cecropin A (1–33). Biochemistry 21:5020–5031CrossRefPubMedGoogle Scholar
  29. Ostolaza H et al (1993) Release of lipid vesicle contents by the bacterial protein toxin α-haemolysin. Biochim Biophys Acta 1147:81–88CrossRefPubMedGoogle Scholar
  30. Otvos L Jr (2005) Antibacterial peptides and proteins with multiple cellular targets. J Pept Sci 11:697–706CrossRefPubMedGoogle Scholar
  31. Otvos L Jr et al (2006) Prior antibacterial peptide-mediated inhibition of protein folding in bacteria mutes resistance enzymes. Antimicrob Agents Chemother 50:3146–3149CrossRefPubMedGoogle Scholar
  32. Pittet D et al (2008) Infection control as a major World Health Organization priority for developing countries. J Hosp Infect 68:285–292CrossRefPubMedGoogle Scholar
  33. Pokorny A, Almeida PF (2004) Kinetics of dye efflux and lipid flip-flop induced by delta-lysin in phosphatidylcholine vesicles and the mechanism of graded release by amphipathic, alpha-helical peptides. Biochemistry 43:8846–8857CrossRefPubMedGoogle Scholar
  34. Pokorny A et al (2008) The activity of the amphipathic peptide delta-lysin correlates with phospholipid acyl chain structure and bilayer elastic properties. Biophys J 95:4748–4755CrossRefPubMedGoogle Scholar
  35. Qian S et al (2008) Structure of the alamethicin pore reconstructed by X-ray diffraction analysis. Biophys J 94:3512–3522CrossRefPubMedGoogle Scholar
  36. Rapaport D, Shai Y (1991) Interaction of fluorescently labeled pardaxin and its analogues with lipid bilayers. J Biol Chem 266:23769–23775PubMedGoogle Scholar
  37. Rathinakumar R, Wimley WC (2008) Biomolecular engineering by combinatorial design and high-throughput screening: small, soluble peptides that permeabilize membranes. J Am Chem Soc 130:9849–9858CrossRefPubMedGoogle Scholar
  38. Rathinakumar R, Wimley WC (2010) High-throughput discovery of broad-spectrum peptide antibiotics. FASEB J 24:3232–3238CrossRefPubMedGoogle Scholar
  39. Rathinakumar R, Walkenhorst WF, Wimley WC (2009) Broad-spectrum antimicrobial peptides by rational combinatorial design and high-throughput screening: the importance of interfacial activity. J Am Chem Soc 131:7609–7617CrossRefPubMedGoogle Scholar
  40. Sengupta D et al (2008) Toroidal pores formed by antimicrobial peptides show significant disorder. Biochim Biophys Acta 1778:2308–2317CrossRefPubMedGoogle Scholar
  41. Shai Y (2002) Mode of action of membrane active antimicrobial peptides. Biopolymers 66:236–248CrossRefPubMedGoogle Scholar
  42. Steiner H et al (1981) Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature 292:246–248CrossRefPubMedGoogle Scholar
  43. Wang Z, Wang G (2004) APD: the antimicrobial peptide database. Nucleic Acids Res 32:590–592CrossRefGoogle Scholar
  44. Westerhoff HV et al (1989) Magainins and the disruption of membrane-linked free-energy transduction. Proc Natl Acad Sci USA 86:6597–6601CrossRefPubMedGoogle Scholar
  45. White SH, Wimley WC, Selsted ME (1995) Structure, function, and membrane integration of defensins. Curr Opin Struct Biol 5:521–527CrossRefPubMedGoogle Scholar
  46. Wimley WC (2010) Describing the mechanism of antimicrobial peptide action with the interfacial activity model. ACS Chem Biol 5:905–917CrossRefPubMedGoogle Scholar
  47. Yeaman MR, Yount NY (2003) Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev 55:27–55CrossRefPubMedGoogle Scholar
  48. Yount NY, Yeaman MR (2004) Multidimensional signatures in antimicrobial peptides. Proc Natl Acad Sci USA 101:7363–7368CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of BiochemistryTulane University Health Sciences CenterNew OrleansUSA
  2. 2.Department of Materials Science and EngineeringThe Johns Hopkins UniversityBaltimoreUSA

Personalised recommendations