Therapeutic Potential of Antimicrobial Peptides

  • Francesc Rabanal
  • Yolanda Cajal


The emergence of pathogens which are resistant or multi-drug resistant to most of the currently available antibiotics is posing an immense burden to the healthcare systems throughout the world. The development of new classes of antibiotics has also suffered a decline since many pharmaceutical companies have gradually abandoned the field. Fortunately, several public–private initiatives to spur the development of new antibiotics have been recently launched. Antimicrobial peptides are thus attracting a renewed interest as potential therapeutic antibiotic candidates. In fact, some of the oldest available antibiotics in the market are cyclic antimicrobial peptides, such as polymyxin B, colistin, gramicidin or bacitracin. However, pharmacological and toxicological problems associated with the systemic use of antimicrobial peptides are slowing their development and drug approval. An overview of the advantages and drawbacks of antimicrobial peptides as antibiotic drugs and a report of compounds that are in development are described.


Antimicrobial Peptide Infective Endocarditis Cyclic Peptide Peptide Drug Skin Structure Infection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank the support of Generalitat de Catalunya (VAL-TEC 08-1-0016, ACC10), MICINN-MINECO (CTQ2008-06200), Fundació Bosch i Gimpera (UB) and Xarxa de Referència en Biotecnologia (XRB). The authors (FR and YC) are members of the ENABLE (European Gram-Negative Antibacterial Engine) European consortium (IMI-ND4BB,


  1. Adenium Biotech (2016). Accessed 25 Feb 2016
  2. Afacan NJ, Yeung ATY, Pena OM et al (2012) Therapeutic potential of host defense peptides in antibiotic-resistant infections. Curr Pharm Des 18:807–819CrossRefPubMedGoogle Scholar
  3. Bocchinfuso G, Bobone S, Mazzuca C et al (2011) Fluorescence spectroscopy and molecular dynamics simulations in studies on the mechanism of membrane destabilization by antimicrobial peptides. Cell Mol Life Sci 68:2281–2301CrossRefPubMedGoogle Scholar
  4. Boucher HW, Talbot GH, DlK Benjamin Jr et al (2013) Infectious diseases society of America. 10x‘20 progress—development of new drugs active against Gram-negative bacilli: an update from the infectious diseases society of America. Clin Infect Dis 56:1685–1694CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bray BL (2003) Large-scale manufacture of peptide therapeutics by chemical synthesis. Nat Rev Drug Discov 2:587–593CrossRefPubMedGoogle Scholar
  6. Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3:238–250CrossRefPubMedGoogle Scholar
  7. Brogden NK, Brogden KA (2011) Will new generations of modified antimicrobial peptides improve their potential as pharmaceuticals? Int J Antimicrob Agents 38:217–225PubMedPubMedCentralGoogle Scholar
  8. Brotz H, Sahl HG (2000) New insights into the mechanism of action of lantibiotics—diverse biological effects by binding to the same molecular target. J Antimicrob Chemother 46:1–6CrossRefPubMedGoogle Scholar
  9. Brotz H, Bierbaum G, Leopold K et al (1998) The lantibiotic mersacidin inhibits peptidoglycan synthesis by targeting lipid II. Antimicrob Agents Chemother 42:154–160PubMedPubMedCentralGoogle Scholar
  10. Butler MS, Blaskovich MA, Cooper MA (2013) Antibiotics in the clinical pipeline in 2013. J Antibiot 66:571–591CrossRefPubMedGoogle Scholar
  11. Cajal Y, Jain MK (1997) Synergism between mellitin and phospholipase A2 from bee venom: apparent activation by intervesicle exchange of phospholipids. Biochemistry 36:3882–3893CrossRefPubMedGoogle Scholar
  12. Cajal Y, Rogers J, Berg O et al (1996a) Intermembrane molecular contacts by polymyxin B mediate exchange of phospholipids. Biochemistry 35:299–308CrossRefPubMedGoogle Scholar
  13. Cajal Y, Ghanta J, Easwaran K et al (1996b) Specificity for the exchange of phospholipids through polymyxin B mediated intermembrane molecular contacts. Biochemistry 35:5684–5695CrossRefPubMedGoogle Scholar
  14. Cantab Anti-infectives (2015). Accessed 25 Feb 2016
  15. CDC (2014) Antibiotic resistant threats in the US 2013. Centre for disease control and prevention, Atlanta. Accessed 25 Feb 2016
  16. Cellceutix (2016). Accessed 25 Feb 2016
  17. Chen CZ, Cooper SL (2002) Interactions between dendrimer biocides and bacterial membranes. Biomaterials 23:3359–3368CrossRefPubMedGoogle Scholar
  18. Clausell A, Rabanal F, Garcia-Subirats M et al (2006) Membrane association and contact formation by a synthetic analog of polymyxin B and its fluorescent derivatives. J Phys Chem B 110:4465–4471CrossRefPubMedGoogle Scholar
  19. Clausell A, Rabanal F, Garcia-Subirats M et al (2007) Gram-negative outer and inner membrane models: insertion of cyclic cationic lipopeptides. J Phys Chem B 111:551–556CrossRefPubMedGoogle Scholar
  20. Cubicin webpage (2014). Accessed 20 Mar 2015
  21. Cutanea Life Sciences (2012). Accessed 25 Feb 2016
  22. Davies J, Davies D (2010) Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 74:417–433CrossRefPubMedPubMedCentralGoogle Scholar
  23. Dipexium Pharmaceuticals (2016). Accessed 25 Feb 2016
  24. Domingues TM, Mattei B, Seelig J et al (2013) Interaction of the antimicrobial peptide gomes in with model membranes: a calorimetric study. Langmuir 29:8609–8618CrossRefPubMedGoogle Scholar
  25. Epand RM, Rotem S, Mor A et al (2008) Bacterial membranes as predictors of antimicrobial potency. J Am Chem Soc 130:14346–14352CrossRefPubMedGoogle Scholar
  26. Falagas ME, Kasiakou SK (2005) Colistin: the revival of polymyxins for the management of multidrug-resistant Gram-negative bacterial infections. Clin Infect Dis 40:1333–1341CrossRefPubMedGoogle Scholar
  27. Falla TJ, Karunaratne DN, Hancock REW (1996) Mode of action of the antimicrobial peptide indolicidin. J Biol Chem 271:19298–19303CrossRefPubMedGoogle Scholar
  28. Finlay BB, Hancock REW (2004) Can innate immunity be enhanced to treat microbial infections? Nat Rev Microbiol 2:497–504CrossRefPubMedGoogle Scholar
  29. Fjell CD, His JA, Hancock REW et al (2012) Designing antimicrobial peptides: form follows function. Nat Rev Drug Discov 11:37–51Google Scholar
  30. Fosgerau K, Hoffman T (2015) Peptide therapeutics: current status and future directions. Drug Discov Today 20:122–128CrossRefPubMedGoogle Scholar
  31. Fox JL (2013) Antimicrobial peptides stage a comeback. Nat Biotech 31:379–382CrossRefGoogle Scholar
  32. Giacometti A, Cirioni O, Barchiesi F et al (1999) In-vitro activity of cationic peptides alone and in combination with clinically used antimicrobial agents against pseudomonas aeruginosa. J Antimicrob Chemother 44:641–645CrossRefPubMedGoogle Scholar
  33. Gilbert DN, Guidos RJ, Boucher HW et al (2010) The 10x‘20 initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis 50:1081–1083CrossRefGoogle Scholar
  34. Goodwin D, Simerska P, Toth I (2012) Peptides as therapeutics with enhanced bioactivity. Curr Med Chem 19:4451–4461CrossRefPubMedGoogle Scholar
  35. Grau-Campistany A,  Manresa A, Pujol M, Rabanal F, Cajal Y (2016) Tryptophan-containing lipopeptide antibiotics derived from polymyxin B with activity against Gram positive and Gram negative bacteria. Biochim Biophys Acta-Biomembranes 1858:333–343Google Scholar
  36. Grau-Campistany A, Pujol M, Marqués, AM, Manresa A, Rabanal F, Cajal  Y (2015) Membrane interaction of a new synthetic antimicrobial lipopeptide sp-85 with broad spectrum activity. Colloids and Surfaces A: Physicochem Eng Aspects 480:307–317Google Scholar
  37. Hale JD, Hancock REW (2007) Alternative mechanisms of action of cationic antimicrobial peptides on bacteria. Expert Rev Anti Infect Ther 5:951–959CrossRefPubMedGoogle Scholar
  38. Hallock KJ, Lee DK, Ramamoorthy A (2003) MSI-78, an analogue of the Magainin antimicrobial peptides, disrupts lipid bilayer structure via positive curvature strain. Biophys J 84:3052–3060CrossRefPubMedPubMedCentralGoogle Scholar
  39. Hancock REW (1997) Peptide antibiotics. Lancet 349:418–4122CrossRefPubMedGoogle Scholar
  40. Hancock REW (2001) Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infect Dis 1:156–164CrossRefPubMedGoogle Scholar
  41. Hancock REW, Scott MG (2000) The role of antimicrobial peptides in animal defences. Proc Natl Acad Sci USA 97:8856–8861CrossRefPubMedPubMedCentralGoogle Scholar
  42. Herper M (2013) How much does pharmaceutical innovation cost? A look at 100 companies. Accessed 25 Feb 2016
  43. Hurdle JG, O’Neill AJ, Chopra I et al (2011) Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat Rev Microbiol 9:62–75CrossRefPubMedPubMedCentralGoogle Scholar
  44. Imlay JA (2013) The molecular mechanisms and physiological consequences of oxidative stress: lessons from a model bacterium. Nat Rev Microbiol 11:443–454CrossRefPubMedPubMedCentralGoogle Scholar
  45. Joint Programming Initiative on Antimicrobial Resistance (2015). Accessed 28 Mar 2015
  46. Jung D, Powers JP, Straus SK et al (2008) Lipid-specific binding of the calcium-dependent antibiotic daptomycin leads to changes in lipid polymorphism of model membranes. Chem Phys Lipids 154:120–128CrossRefPubMedGoogle Scholar
  47. Klevens RM, Morrison MA, Nadle J et al (2007) Invasive methicillin-resistant Staphylococcous aureus infection in the United States. JAMA 298:1763–1771CrossRefPubMedGoogle Scholar
  48. Knight-Connoni V, Carmela Mascio C, Chesnel L, Silverman J (2016) Discovery and development of surotomycin for the treatment of Clostridium difficile. J Ind Microbiol Biotechnol 43:195–204Google Scholar
  49. Lan Y, Ye Y, Kozlowska J et al (2010) Structural contributions to the intracellular targeting strategies of antimicrobial peptides. Biochim Biophys Acta 1798:1934–1943CrossRefPubMedPubMedCentralGoogle Scholar
  50. Laverty G, Gorman SP, Gilmor BF (2011) The potential of antimicrobial peptides as biocides. Int J Mol Sci 12:6566–6596CrossRefPubMedPubMedCentralGoogle Scholar
  51. Lytix Biopharma (2016). Accessed 25 Feb 2016
  52. Magee TV, Brown MF, Starr JT et al (2013) Discovery of dap-3 polymyxin analogues for the treatment of multidrug-resistant Gram-negative nosocomial infections. J Med Chem 56:5079–5093CrossRefPubMedGoogle Scholar
  53. Marchand C, Krajewski K, Lee HF et al (2006) Covalent binding of the natural antimicrobial peptide indolicidin to DNA abasic sites. Nucleic Acids Res 34:5157–5165CrossRefPubMedPubMedCentralGoogle Scholar
  54. Nguyen LT, Haney EF, Vogel HJ (2011) The expanding scope of antimicrobial peptide structures and their modes of action. Trends Biotechnol 29:464–472CrossRefPubMedGoogle Scholar
  55. Novabiotics (2014). Accessed 25 Feb 2016
  56. Novactabio (2014). Accessed 25 Feb 2016
  57. Oh JT, Van Dyk TK, Cajal Y et al (1998a) Osmotic stress in viable Escherichia coli as the basis for the antibiotic response to polymyxin B. Biochem Biophys Res Commun 246:619–623CrossRefPubMedGoogle Scholar
  58. Oh JT, Cajal Y, Dhurjati PS et al (1998b) Cecropins induce the hyperosmotic stress response in Escherichia coli. Biochim Biophys Acta 1415:235–245CrossRefPubMedGoogle Scholar
  59. Oh JT, Cajal Y, Skowronska EM et al (2000) Cationic peptide antimicrobials induce selective transcription of micF and osmY in Escherichia coli. Biochim Biophys Acta 1463:43–54CrossRefPubMedGoogle Scholar
  60. Oragenics (2016). Accessed 25 Feb 2016
  61. Oren Z, Shai Y (1998) Mode of action of linear amphipathic alpha-helical antimicrobial peptides. Biopolymers 47:451–463CrossRefPubMedGoogle Scholar
  62. Park CB, Kim HS, Kim SC (1998) Mechanism of action of the antimicrobial peptide buforin II: buforin II kills microorganisms by penetrating the cell membrane and inhibiting cellular functions. Biochem Biophys Res Commun 244:253–257CrossRefPubMedGoogle Scholar
  63. Pasupuleti M, Schmidtchen A, Malmsten M (2012) Antimicrobial peptides: key components of the innate immune system. Crit Rev Biotechnol 32:143–171CrossRefPubMedGoogle Scholar
  64. Pergamum AB (2016). Accessed 25 Feb 2016
  65. Polyphor (2015). Accessed 25 Feb 2016
  66. Rabanal F, Grau-Campistany A, Vila-Farrés X et al (2015). A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity. Scientific Reports 5:10558Google Scholar
  67. Rex JH (2014) ND4BB: addressing the antimicrobial resistance crisis. Nat Rev Microbiol 12:231–232CrossRefGoogle Scholar
  68. Rokitskaya TI, Kolodkin NI, Kotova EA et al (2011) Indolicidin action on membrane permeability: carrier mechanism versus pore formation. Biochim Biophys Acta 1808:91–97CrossRefPubMedGoogle Scholar
  69. Saberwal G, Nagaraj R (1994) Cell-lytic and antibacterial peptides that act by perturbing the barrier function of membranes: facets of their conformational features, structure-function correlations and membrane-perturbing abilities. Biochim Biophys Acta 1197:109–131CrossRefPubMedGoogle Scholar
  70. Sawyer JG, Martin NL, Hancock REW (1988) Interaction of macrophage cationic proteins with the outer membrane of Pseudomonas aeruginosa. Infect Immun 56:693–698PubMedPubMedCentralGoogle Scholar
  71. Silverman JA, Perlmutter NG, Shapiro HM (2003) Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrob Agents Chemother 47:2538–2544CrossRefPubMedPubMedCentralGoogle Scholar
  72. Soligenix (2016). Accessed 25 Feb 2016
  73. Spaar A, Munster C, Salditt T (2004) Conformation of peptides in lipid membranes studied by X-ray grazing incidence scattering. Biophys J 87:396–407CrossRefPubMedPubMedCentralGoogle Scholar
  74. Srinivas NP, Jetter P, Ueberbacher BJ et al (2010) Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science 327:1010–1013CrossRefPubMedGoogle Scholar
  75. Stevenson CL (2009) Advances in peptide pharmaceuticals. Curr Pharm Biotech 10:122–1237CrossRefGoogle Scholar
  76. Straus SK, Hancock REW (2006) Mode of action of the new antibiotic for Gram-positive pathogens daptomycin: comparison with cationic antimicrobial peptides and lipopeptides. Biochim Biophys Acta 1758:1215–1223CrossRefPubMedGoogle Scholar
  77. Sun J, Xia Y, Li D et al (2014) Relationship between peptide structure and antimicrobial activity as studied by de novo designed peptides. Biochim Biophys Acta 1838:2985–2993CrossRefPubMedGoogle Scholar
  78. The Pew Charitable Trusts (2015) Antibiotics Currently in Clinical Development. Accessed 25 Feb 2016.
  79. Toke O (2005) Antimicrobial peptides: new candidates in the fight against bacterial infections. Biopolymers 80:717–735CrossRefPubMedGoogle Scholar
  80. Tufts Center for the Study of Drug Development (2014). Accessed 25 Mar 2014
  81. Uhlig T, Kyprianou T, Martinelli FG et al (2014) The emergence of peptides in the pharmaceutical business: from exploration to exploitation. Eur Proteomics Assoc (EuPA) 4:58–69Google Scholar
  82. Vaara M (2013) Novel derivatives of polymyxins. J Antimicrob Chemother 68:1213–1219CrossRefPubMedGoogle Scholar
  83. Van Epps HL (2006) René Dubos: unearthing antibiotics. J Exp Med 203:259CrossRefPubMedPubMedCentralGoogle Scholar
  84. Velkov T, Thompson PE, Nation RL et al (2010) Structure-activity relationships of polymyxin antibiotics. J Med Chem 53:1898–1916CrossRefPubMedPubMedCentralGoogle Scholar
  85. Velkov T, Roberts KD, Nation RL et al (2014) Teaching ‘old’ polymyxins new tricks: new-generation lipopeptides targeting Gram-negative ‘superbugs’. ACS Chem Biol 9:1172–1177CrossRefPubMedPubMedCentralGoogle Scholar
  86. Viñas M, Rabanal F, Benz R et al (2014) Perspectives in the research of antimicrobial peptides. In: Veiga-Crespo P, Villa TG (eds) Antimicrobial compounds: current strategies and new alternatives, 1st edn. Springer, Berlin, pp 269–284CrossRefGoogle Scholar
  87. Wade D, Boman A, Wahlin B et al (1990) All-d amino acid-containing channel-forming antibiotic peptides. Proc Natl Acad Sci USA 87:4761–4765CrossRefPubMedPubMedCentralGoogle Scholar
  88. Walsh CT, Wencewicz TA (2014) Prospects for new antibiotics: a molecule-centered perspective. J Antibiot 67:7–22CrossRefPubMedGoogle Scholar
  89. WHO (2014) Antimicrobial resistance: global report on surveillance 2014. World Health Organization. Accessed 25 Mar 2015
  90. Yang L, Harroun TA, Weiss TM et al (2001) Barrel-stave model or toroidal model? A case study on melittin pores. Biophys J 81:1475–1485CrossRefPubMedPubMedCentralGoogle Scholar
  91. Yeaman MR, Yount NY (2003) Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev 55:27–55CrossRefPubMedGoogle Scholar
  92. Yount NY, Yeaman MR (2012) Emerging themes and therapeutic prospects for anti-infective peptides. Annu Rev Pharmacol Toxicol 52:337–360CrossRefPubMedGoogle Scholar
  93. Yu Z, Qin W, Lin J et al (2015) Antibacterial mechanisms of polymyxin and bacterial resistance. BioMed Res Int 2015:1–12Google Scholar
  94. Zhang L, Pornpattananangkul D, Hu C-MJ, Huang C (2010) Development of nanoparticles for antimicrobial drug delivery. Curr Med Chem 17:585–594CrossRefPubMedGoogle Scholar
  95. Zhao H, Mattila JP, Holopainen JM et al (2001) Comparison of the membrane association of two antimicrobial peptides, magainin 2 and indolicidin. Biophys J 81:2979–2991CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Organic Chemistry, Faculty of ChemistryUniversity of BarcelonaBarcelonaSpain
  2. 2.Department of Physical Chemistry, Faculty of Pharmacy and Nanoscience and Nanotechnology Institute IN2UBUniversity of BarcelonaBarcelonaSpain

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