Simple oligomers as antimicrobial peptide mimics

  • Jason Rennie
  • Lachelle Arnt
  • Haizhong Tang
  • Klaus NüssleinEmail author
  • Gregory N. Tew
Special Topic: Disinfectants and Microbial Control


New approaches to antibiotic design are desperately needed. The design of simple oligomers that capture the shape and biological function of natural antimicrobial peptides could prove to be versatile and highly successful. We discuss the use of aromatic backbones to design facially amphiphilic (FA) β-sheet like structures which are potently antimicrobial. These oligomers capture the physiochemical properties of peptides like the Magainins and Defensins, which fold into specific conformations that are amphiphilic resulting in antimicrobial activity. However, natural peptides are expensive to prepare and difficult to produce on large scale. The design of polymers and oligomers that mimic the complex structures and remarkable biological properties of proteins is an important endeavor and provides attractive alternatives to the difficult synthesis of natural peptides. We therefore have designed a series of FA oligomers that are easy to prepare from inexpensive monomers. They adopt structures very reminiscent of amphiphilic β-sheets and have significant activity with minimal inhibitory concentrations at 6 h in the low microgram per ml range (μM to nM). They are active against a broad spectrum of bacteria including gram-positive and gram-negative as well as antibiotic resistant strains.


Magainin Host defense peptides Phenylene ethynylene Facially amphiphilic Antibacterial 



This work was supported in part by the National Science Foundation Biocomplexity Program (CHE-0221791) to K.N., the National Institutes of Health (GM-065803) and ONR Young Investigator (N00014-03-1-0503) to G.N.T. G.N.T gratefully acknowledges the PECASE program, ARO for a Young Investigator Award, 3M Nontenured Faculty Award, and DuPont Young Faculty Grant.


  1. 1.
    Albert M, Feiertag P, Hayn G, Saf R, Honig H (2003) Structure-activity relationships of oligoguanidines-influence of counterion, diamine, and average molecular weight on blocidal activities. Biomacromolecules 4:1811–1817CrossRefPubMedGoogle Scholar
  2. 2.
    Arnt L, Nüsslein K, Tew GN (2004) Nonhemolytic abiogenic polymers as antimicrobial peptide mimics. J Polym Sci Polym Chem 42:3860–3864CrossRefGoogle Scholar
  3. 3.
    Arnt L, Tew GN (2002) New poly(phenyleneethynylene)s with cationic, facially amphiphilic structures. J Am Chem Soc 124:7664–7665CrossRefPubMedGoogle Scholar
  4. 4.
    Arnt L, Tew GN (2003) Facially amphiphilic poly(phenyleneethynylene)s studied at the air-water interface. Langmuir 19:2404–2408CrossRefGoogle Scholar
  5. 5.
    Boman HG (2000) Innate immunity and the normal microflora. Immunol Rev 173:5–16CrossRefPubMedGoogle Scholar
  6. 6.
    DeGrado WF (1988) Design of peptides and proteins. Adv Protein Chem 39:51–124PubMedGoogle Scholar
  7. 7.
    Doerksen RJ, Chen B, Liu D, Tew G, DeGrado WF, Klein ML (2004) Controlling the conformation of arylamides: computational studies of intramolecular hydrogen bonds between amides and ethers or thioethers. Chem Eur J 10:5008–5016CrossRefGoogle Scholar
  8. 8.
    Gellman SH (1998) Foldamers: a manifesto. Acc Chem Res 31:173–180CrossRefGoogle Scholar
  9. 9.
    Gelman MA, Weisblum B, Lynn DM, Gellman SH (2004) Biocidal activity of polystyrenes that are cationic by virtue of protonation. Org Lett 6:557–560CrossRefPubMedGoogle Scholar
  10. 10.
    Hancock RE, Chapple DS (1999) Peptide antibiotics. Antimicrob Agents Chemother 43:1317–1323PubMedGoogle Scholar
  11. 11.
    Hancock RE, Lehrer R (1998) Cationic peptides: a new source of antibiotics. Trends Biotechnol 16:82–88CrossRefPubMedGoogle Scholar
  12. 12.
    Ho CH, Tobis J, Sprich C, Thomann R, Tiller JC (2004) Nanoseparated polymeric networks with multiple antimicrobial properties. Adv Mater 16:957–959CrossRefGoogle Scholar
  13. 13.
    Ilker MF, Nüsslein K, Tew GN, Coughlin EB (2004) Tuning the hemolytic and antibacterial activities of amphiphilic polynorbornene derivatives. J Am Chem Soc 126:15870–15875PubMedGoogle Scholar
  14. 14.
    Kenawy ER, Abdel-Hay FI, El-Shanshoury A, El-Newehy MH (2002) Biologically active polymers. V. Synthesis and antimicrobial activity of modified poly(glycidyl methacrylate-co-2-hydroxyethyl methacrylate) derivatives with quaternary ammonium and phosphonium salts. J Polym Sci Polym Chem 40:2384–2393CrossRefGoogle Scholar
  15. 15.
    Miller SM, Simon RJ, Ng S, Zuckerman RN, Kerr JM, Moos WH (1995) Comparison of the proteolytic susceptibilities of homologous l-amino acid, d-amino acid, and N-substituted glycine peptide and peptoid oligomers. Drug Dev Res 35:20–32CrossRefGoogle Scholar
  16. 16.
    Oh ST, Han SH, Ha CS, Cho WJ (1996) Synthesis and biocidal activities of polymer. IV. Antibacterial activity and hydrolysis of polymers containing diphenyl ether. J Appl Polym Sci 59:1871–1878CrossRefGoogle Scholar
  17. 17.
    Oren Z, Shai Y (1998) Mode of action of linear amphipathic alpha-helical antimicrobial peptides. Biopolymers 47:451–463CrossRefPubMedGoogle Scholar
  18. 18.
    Patch JA, Barron AE (2003) Helical peptoid mimics of magainin-2 amide. J Am Chem Soc 125:12092–12093CrossRefPubMedGoogle Scholar
  19. 19.
    Patel MB, Patel SA, Ray A, Patel R M (2003) Synthesis, characterization, and antimicrobial activity of acrylic copolymers. J Appl Polym Sci 89:895–900CrossRefGoogle Scholar
  20. 20.
    Popa A, Davidescu CM, Trif R, Ilia G, Iliescu S, Dehelean G (2003) Study of quaternary ’onium’ salts grafted on polymers: antibacterial activity of quaternary phosphonium salts grafted on ’gel-type’ styrene-divinylbenzene copolmyers. Reactive Funct Poly 55:151–158CrossRefGoogle Scholar
  21. 21.
    Porter EA, Wang X, Lee HS, Weisblum B, Gellman SH (2000) Non-haemolytic beta-amino-acid oligomers. Nature (London) 404:565CrossRefGoogle Scholar
  22. 22.
    Porter EA, Weisblum B, Gellman SH (2002) Mimicry of host-defense peptides by unnatural oligomers: antimicrobial beta-peptides. J Am Chem Soc 124:7324–7330CrossRefPubMedGoogle Scholar
  23. 23.
    Raguse TL, Porter EA, Weisblum B, Gellman SH (2002) Structure-activity studies of 14-helical antimicrobial beta-peptides: probing the relationship between conformational stability and antimicrobial potency. J Am Chem Soc 124:12774–12785CrossRefPubMedGoogle Scholar
  24. 24.
    Rivas BL, Pereira ED, Mondaca MA, Rivas RJ, Saavedra MA (2003) Water-soluble cationic polymers and their polymer-metal complexes with biocidal activity: a genotoxicity study. J Appl Polym Sci 87:452–457CrossRefGoogle Scholar
  25. 25.
    Sauvet G, Fortuniak W, Kazmierski K, Chojnowski J (2003) Amphiphilic block and statistical siloxane copolymers with antimicrobial activity. J Polym Sci Polym Chem 41:2939–2948CrossRefGoogle Scholar
  26. 26.
    Solomon S, Horan T, Andrus M, Edwards J, Fridkin S, Koganti J, Peavy G, Tolson J (2003) National nosocomial infections surveillance system. Am J Infect Control 31:481–498CrossRefPubMedGoogle Scholar
  27. 27.
    Tang H, Doerksen RJ, Jones TV, Klein ML, Tew GN (2005) Intramolecular hydrogen bonded oligomers based on 4,6 dicarboxy pyrimidine are facially amphiphilic and antibacterial. (submitted)Google Scholar
  28. 28.
    Tashiro T (2001) Antibacterial and bacterium adsorbing macromolecules. Macromol Mater Eng 286:63–87CrossRefGoogle Scholar
  29. 29.
    Tew GN, Liu DH, Chen B, Doerksen RJ, Kaplan J, Carroll PJ, Klein ML, DeGrado WF (2002) De novo design of biomimetic antimicrobial polymers. Proc Natl Acad Sci USA 99:5110–5114CrossRefPubMedGoogle Scholar
  30. 30.
    Tiller JC, Liao CJ, Lewis K, Klibanov AM (2001) Designing surfaces that kill bacteria on contact. Proc Natl Acad Sci USA 98:5981–5985CrossRefPubMedGoogle Scholar
  31. 31.
    Tossi A, Sandri L, Giangaspero A (2000) Amphipathic alpha-helical antimicrobial peptides. Biopolymers 55:4–30CrossRefPubMedGoogle Scholar
  32. 32.
    Waschinski CJ, Tiller JC (2005) Poly(oxazoline)s with telechelic antimicrobial functions. Biomacromolecules 6:235–243CrossRefPubMedGoogle Scholar
  33. 33.
    Woo GLY, Mittelman MW, Santerre JP (2000) Synthesis and characterization of a novel biodegradable antimicrobial polymer. Biomaterials 21:1235–1246CrossRefPubMedGoogle Scholar
  34. 34.
    Worley SD, Sun G (1996) Biocidal polymers. Trends Polym Sci 4:364–370Google Scholar
  35. 35.
    Worley SD, Li F, Wu R, Kim J, Wei CI, Williams JF, Owens JR, Wander JD, Bargmeyer AM, Shirtliff ME (2003) A novel N-halamine monomer for preparing biocidal polyurethane coatings. Surf Coat Inter B Coat Trans 86:273–277Google Scholar
  36. 36.
    Wu CW, Sanborn TJ, Huang K, Zuckerman RN, Barron AE (2001) Peptoid oligomers with alpha-chiral, aromatic side chains: sequence requirements for the formation of stable peptoid helices. J Am Chem Soc 123:6778–6784CrossRefPubMedGoogle Scholar
  37. 37.
    Wu CW, Sanborn TJ, Zuckerman RN, Barron AE (2001) Peptoid oligomers with alpha-chiral, aromatic side chains: effects of chain length on secondary structure. J Am Chem Soc 123:2958–2963CrossRefPubMedGoogle Scholar
  38. 38.
    Zasloff M (1992) Antibiotic peptides as mediators of innate immunity. Curr Opin Immunol 4:3–7CrossRefPubMedGoogle Scholar
  39. 39.
    Zasloff M (2002) Antimicrobial peptides of multicellular organisms. Nature (London) 415:389–395Google Scholar

Copyright information

© Society for Industrial Microbiology 2005

Authors and Affiliations

  • Jason Rennie
    • 1
  • Lachelle Arnt
    • 2
  • Haizhong Tang
    • 2
  • Klaus Nüsslein
    • 1
    Email author
  • Gregory N. Tew
    • 2
  1. 1.Department of MicrobiologyUniversity of MassachusettsAmherstUSA
  2. 2. Polymer Science and Engineering DepartmentUniversity of MassachusettsAmherstUSA

Personalised recommendations