Amino Acids

, Volume 47, Issue 12, pp 2505–2519 | Cite as

d-Amino acids incorporation in the frog skin-derived peptide esculentin-1a(1-21)NH2 is beneficial for its multiple functions

  • Antonio Di Grazia
  • Floriana Cappiello
  • Hadar Cohen
  • Bruno Casciaro
  • Vincenzo Luca
  • Alessandro Pini
  • Y. Peter Di
  • Yechiel Shai
  • Maria Luisa MangoniEmail author
Original Article


Naturally occurring antimicrobial peptides (AMPs) represent promising future antibiotics. We have previously isolated esculentin-1a(1-21)NH2, a short peptide derived from the frog skin AMP esculentin-1a, with a potent anti-Pseudomonal activity. Here, we investigated additional functions of the peptide and properties responsible for these activities. For that purpose, we synthesized the peptide, as well as its structurally altered analog containing two d-amino acids. The peptides were then biophysically and biologically investigated for their cytotoxicity and immunomodulating activities. The data revealed that compared to the wild-type, the diastereomer: (1) is significantly less toxic towards mammalian cells, in agreement with its lower α-helical structure, as determined by circular dichroism spectroscopy; (2) is more effective against the biofilm form of Pseudomonas aeruginosa (responsible for lung infections in cystic fibrosis sufferers), while maintaining a high activity against the free-living form of this important pathogen; (3) is more stable in serum; (4) has a higher activity in promoting migration of lung epithelial cells, and presumably in healing damaged lung tissue, and (5) disaggregates and detoxifies the bacterial lipopolysaccharide (LPS), albeit less than the wild-type. Light scattering studies revealed a correlation between anti-LPS activity and the ability to disaggregate the LPS. Besides shedding light on the multifunction properties of esculentin-1a(1-21)NH2, the d-amino acid containing isomer may serve as an attractive template for the development of new anti-Pseudomonal compounds with additional beneficial properties. Furthermore, together with other studies, incorporation of d-amino acids may serve as a general approach to optimize the future design of new AMPs.


Diastereomer Wound healing Anti-biofilm activity Antimicrobial peptide Esculentin-1 



Antimicrobial peptide


Circular dichroism


Colony-forming units


Dulbecco’s modified Eagle’s medium supplemented with glutamine


Heat-inactivated fetal bovine serum


Luria–Bertani broth






3(4,5-Dimethylthiazol-2yl)2,5-diphenyltetrazolium bromide


Phosphate buffered saline



The authors thank Silvia Scali (University of Siena, Italy) for the help in the peptides stability studies as well as Dr. Alessandra Bragonzi (San Raffaele Institute, Milan, Italy) and Professor Burkhard Tummler (Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Hannover, Germany) for the P. aeruginosa clinical isolates. This work was supported by grants from Sapienza Università di Roma and the Italian Foundation for Cystic Fibrosis (Project FFC#11/2014 adopted by FFC Delegations from Siena, Sondrio Valchiavenna, Cerea Il Sorriso di Jenny and Pavia). The Ordine Nazionale dei Biologi is acknowledged for the fellowship provided to V.L. Y. Shai is incumbents of The Harold S. and Harriet B. Brady Professorial Chair in Cancer Research. Part of the content of this work is object of a US patent application N. 14/506,383.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Akram KM, Samad S, Spiteri MA, Forsyth NR (2013) Mesenchymal stem cells promote alveolar epithelial cell wound repair in vitro through distinct migratory and paracrine mechanisms. Respir Res 14:9PubMedCentralCrossRefPubMedGoogle Scholar
  2. Alba A, Lopez-Abarrategui C, Otero-Gonzalez AJ (2012) Host defense peptides: an alternative as antiinfective and immunomodulatory therapeutics. Biopolymers 98:251–267CrossRefPubMedGoogle Scholar
  3. Baltimore RS, Christie CD, Smith GJ (1989) Immunohistopathologic localization of Pseudomonas aeruginosa in lungs from patients with cystic fibrosis. Implications for the pathogenesis of progressive lung deterioration. Am Rev Respir Dis 140:1650–1661CrossRefPubMedGoogle Scholar
  4. Bevins CL (2013) Innate immune functions of alpha-defensins in the small intestine. Dig Dis 31:299–304CrossRefPubMedGoogle Scholar
  5. Bhunia A, Saravanan R, Mohanram H, Mangoni ML, Bhattacharjya S (2011) NMR structures and interactions of temporin-1Tl and temporin-1Tb with lipopolysaccharide micelles: mechanistic insights into outer membrane permeabilization and synergistic activity. J Biol Chem 286:24394–24406PubMedCentralCrossRefPubMedGoogle Scholar
  6. Bjarnsholt T, Jensen PO, Fiandaca MJ, Pedersen J, Hansen CR, Andersen CB, Pressler T, Givskov M, Hoiby N (2009) Pseudomonas aeruginosa biofilms in the respiratory tract of cystic fibrosis patients. Pediatr Pulmonol 44:547–558CrossRefPubMedGoogle Scholar
  7. Boman HG (1995) Peptide antibiotics and their role in innate immunity. Annu Rev Immunol 13:61–92CrossRefPubMedGoogle Scholar
  8. Bragonzi A, Paroni M, Nonis A, Cramer N, Montanari S, Rejman J, Di Serio C, Doring G, Tummler B (2009) Pseudomonas aeruginosa microevolution during cystic fibrosis lung infection establishes clones with adapted virulence. Am J Respir Crit Care Med 180:138–145CrossRefPubMedGoogle Scholar
  9. Brown KL, Hancock RE (2006) Cationic host defense (antimicrobial) peptides. Curr Opin Immunol 18:24–30CrossRefPubMedGoogle Scholar
  10. Carotenuto A, Malfi S, Saviello MR, Campiglia P, Gomez-Monterrey I, Mangoni ML, Gaddi LM, Novellino E, Grieco P (2008) A different molecular mechanism underlying antimicrobial and hemolytic actions of temporins A and L. J Med Chem 51:2354–2362CrossRefPubMedGoogle Scholar
  11. Ceri H, Olson M, Morck D, Storey D, Read R, Buret A, Olson B (2001) The MBEC assay system: multiple equivalent biofilms for antibiotic and biocide susceptibility testing. Methods Enzymol 337:377–385CrossRefPubMedGoogle Scholar
  12. Chen LF, Chopra T, Kaye KS (2009) Pathogens resistant to antibacterial agents. Infect Dis Clin North Am 23:817–845 vii CrossRefPubMedGoogle Scholar
  13. Chieng-Yane P, Bocquet A, Letienne R, Bourbon T, Sablayrolles S, Perez M, Hatem SN, Lompre AM, Le Grand B, David-Dufilho M (2011) Protease-activated receptor-1 antagonist F 16618 reduces arterial restenosis by down-regulation of tumor necrosis factor alpha and matrix metalloproteinase 7 expression, migration, and proliferation of vascular smooth muscle cells. J Pharmacol Exp Ther 336:643–651CrossRefPubMedGoogle Scholar
  14. Chuquimia OD, Petursdottir DH, Periolo N, Fernandez C (2013) Alveolar epithelial cells are critical in protection of the respiratory tract by secretion of factors able to modulate the activity of pulmonary macrophages and directly control bacterial growth. Infect Immun 81:381–389PubMedCentralCrossRefPubMedGoogle Scholar
  15. Cohen J (2002) The immunopathogenesis of sepsis. Nature 420:885–891CrossRefPubMedGoogle Scholar
  16. Cruz J, Ortiz C, Guzman F, Fernandez-Lafuente R, Torres R (2014) Antimicrobial peptides: promising compounds against pathogenic microorganisms. Curr Med Chem 21:2299–2321CrossRefPubMedGoogle Scholar
  17. Dempsey CE, Hawrani A, Howe RA, Walsh TR (2010) Amphipathic antimicrobial peptides—from biophysics to therapeutics? Protein Pept Lett 17:1334–1344CrossRefPubMedGoogle Scholar
  18. Di Grazia A, Cappiello F, Imanishi A, Mastrofrancesco A, Picardo M, Paus R, Mangoni ML (2015) The frog skin-derived antimicrobial peptide esculentin-1a(1-21)NH2 promotes the migration of human HaCaT keratinocytes in an EGF receptor-dependent manner: a novel promoter of human skin wound healing? PLoS One 10:e0128663PubMedCentralCrossRefPubMedGoogle Scholar
  19. Di Grazia A, Luca V, Segev-Zarko LA, Shai Y, Mangoni ML (2014) Temporins A and B stimulate migration of HaCaT keratinocytes and kill intracellular Staphylococcus aureus. Antimicrob Agents Chemother 58:2520–2527PubMedCentralCrossRefPubMedGoogle Scholar
  20. Drenkard E, Ausubel FM (2002) Pseudomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature 416:740–743CrossRefPubMedGoogle Scholar
  21. Epand RF, Savage PB, Epand RM (2007) Bacterial lipid composition and the antimicrobial efficacy of cationic steroid compounds (Ceragenins). Biochim Biophys Acta 1768:2500–2509CrossRefPubMedGoogle Scholar
  22. Epand RF, Schmitt MA, Gellman SH, Epand RM (2006) Role of membrane lipids in the mechanism of bacterial species selective toxicity by two alpha/beta-antimicrobial peptides. Biochim Biophys Acta 1758:1343–1350CrossRefPubMedGoogle Scholar
  23. Epand RM, Vogel HJ (1999) Diversity of antimicrobial peptides and their mechanisms of action. Biochim Biophys Acta 1462:11–28CrossRefPubMedGoogle Scholar
  24. Falciani C, Lozzi L, Pollini S, Luca V, Carnicelli V, Brunetti J, Lelli B, Bindi S, Scali S, Di Giulio A, Rossolini GM, Mangoni ML, Bracci L, Pini A (2012) Isomerization of an antimicrobial Peptide broadens antimicrobial spectrum to gram-positive bacterial pathogens. PLoS One 7:e46259PubMedCentralCrossRefPubMedGoogle Scholar
  25. Fjell CD, Hiss JA, Hancock RE, Schneider G (2012) Designing antimicrobial peptides: form follows function. Nat Rev Drug Discov 11:37–51Google Scholar
  26. Gamberi T, Cavalieri D, Magherini F, Mangoni ML, De Filippo C, Borro M, Gentile G, Simmaco M, Modesti A (2007) An integrated analysis of the effects of Esculentin 1-21 on Saccharomyces cerevisiae. Biochim Biophys Acta 1774:688–700CrossRefPubMedGoogle Scholar
  27. Gazit E, Lee WJ, Brey PT, Shai Y (1994) Mode of action of the antibacterial cecropin B2: a spectrofluorometric study. Biochemistry 33:10681–10692CrossRefPubMedGoogle Scholar
  28. Ghosh A, Datta A, Jana J, Kar RK, Chatterjee C, Chatterjee S, Bhunia A (2014) Sequence context induced antimicrobial activity: insight into lipopolysaccharide permeabilization. Mol Biosyst 10:1596–1612CrossRefPubMedGoogle Scholar
  29. Giacometti A, Cirioni O, Ghiselli R, Mocchegiani F, Orlando F, Silvestri C, Bozzi A, Di Giulio A, Luzi C, Mangoni ML, Barra D, Saba V, Scalise G, Rinaldi AC (2006) Interaction of antimicrobial peptide temporin L with lipopolysaccharide in vitro and in experimental rat models of septic shock caused by gram-negative bacteria. Antimicrob Agents Chemother 50:2478–2486PubMedCentralCrossRefPubMedGoogle Scholar
  30. Grieco P, Carotenuto A, Auriemma L, Limatola A, Di Maro S, Merlino F, Mangoni ML, Luca V, Di Grazia A, Gatti S, Campiglia P, Gomez-Monterrey I, Novellino E, Catania A (2013) Novel alpha-MSH peptide analogues with broad spectrum antimicrobial activity. PLoS One 8:e61614PubMedCentralCrossRefPubMedGoogle Scholar
  31. Grundmann H, Klugman KP, Walsh T, Ramon-Pardo P, Sigauque B, Khan W, Laxminarayan R, Heddini A, Stelling J (2011) A framework for global surveillance of antibiotic resistance. Drug Resist Updat 14:79–87CrossRefPubMedGoogle Scholar
  32. Guralp SA, Murgha YE, Rouillard JM, Gulari E (2013) From design to screening: a new antimicrobial peptide discovery pipeline. PLoS One 8:e59305PubMedCentralCrossRefPubMedGoogle Scholar
  33. Hamamoto K, Kida Y, Zhang Y, Shimizu T, Kuwano K (2002) Antimicrobial activity and stability to proteolysis of small linear cationic peptides with D-amino acid substitutions. Microbiol Immunol 46:741–749CrossRefPubMedGoogle Scholar
  34. Hancock RE, Nijnik A, Philpott DJ (2012) Modulating immunity as a therapy for bacterial infections. Nat Rev Microbiol 10:243–254CrossRefPubMedGoogle Scholar
  35. Hancock RE, Sahl HG (2006) Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 24:1551–1557CrossRefPubMedGoogle Scholar
  36. Haney EF, Hancock RB (2013) Peptide design for antimicrobial and immunomodulatory applications. Biopolymers 100(572):583Google Scholar
  37. Hoq MI, Niyonsaba F, Ushio H, Aung G, Okumura K, Ogawa H (2011) Human catestatin enhances migration and proliferation of normal human epidermal keratinocytes. J Dermatol Sci 64:108–118CrossRefPubMedGoogle Scholar
  38. Huang LC, Redfern RL, Narayanan S, Reins RY, McDermott AM (2007) In vitro activity of human beta-defensin 2 against Pseudomonas aeruginosa in the presence of tear fluid. Antimicrob Agents Chemother 51:3853–3860PubMedCentralCrossRefPubMedGoogle Scholar
  39. Islas-Rodriguez AE, Marcellini L, Orioni B, Barra D, Stella L, Mangoni ML (2009) Esculentin 1-21: a linear antimicrobial peptide from frog skin with inhibitory effect on bovine mastitis-causing bacteria. J Pept Sci 15:607–614CrossRefPubMedGoogle Scholar
  40. Jung Kim D, Lee YW, Park MK, Shin JR, Lim KJ, Cho JH, Kim SC (2014) Efficacy of the designer antimicrobial peptide SHAP1 in wound healing and wound infection. Amino Acids 46:2333–2343CrossRefPubMedGoogle Scholar
  41. Kai-Larsen Y, Gudmundsson GH, Agerberth B (2014) A review of the innate immune defence of the human foetus and newborn, with the emphasis on antimicrobial peptides. Acta Paediatr 103:1000–1008CrossRefPubMedGoogle Scholar
  42. Kaye KS (2012) Antimicrobial de-escalation strategies in hospitalized patients with pneumonia, intra- abdominal infections, and bacteremia. J Hosp Med 7(Suppl 1):S13–S21CrossRefGoogle Scholar
  43. Knappe D, Henklein P, Hoffmann R, Hilpert K (2010) Easy strategy to protect antimicrobial peptides from fast degradation in serum. Antimicrob Agents Chemother 54:4003–4005PubMedCentralCrossRefPubMedGoogle Scholar
  44. Kolar SS, Luca V, Baidouri H, Mannino G, McDermott AM, Mangoni ML (2015) Esculentin-1a(1-21)NH: a frog skin-derived peptide for microbial keratitis. Cell Mol Life Sci 72:617–627CrossRefPubMedGoogle Scholar
  45. Levitzki A, Gazit A (1995) Tyrosine kinase inhibition: an approach to drug development. Science 267:1782–1788CrossRefPubMedGoogle Scholar
  46. Li J, Turnidge J, Milne R, Nation RL, Coulthard K (2001) In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother 45:781–785PubMedCentralCrossRefPubMedGoogle Scholar
  47. Lohner K, Staudegger E (2001) Are we on the threshold of the post-antibiotic era? In: Lohner K (ed) Development of novel antimicrobial agents: emerging strategies. Horizon Scientific Press, Wymondham, pp 1–15Google Scholar
  48. Luca V, Stringaro A, Colone M, Pini A, Mangoni ML (2013) Esculentin(1-21), an amphibian skin membrane-active peptide with potent activity on both planktonic and biofilm cells of the bacterial pathogen Pseudomonas aeruginosa. Cell Mol Life Sci 70:2773–2786CrossRefPubMedGoogle Scholar
  49. Luca V, Olivi M, Di Grazia A, Palleschi C, Uccelletti D, Mangoni ML (2014) Anti-Candida activity of 1-18 fragment of the frog skin peptide esculentin-1b: in vitro and in vivo studies in a Caenorhabditis elegans infection model. Cell Mol Life Sci 71:2535–2546PubMedGoogle Scholar
  50. Macia MD, Rojo-Molinero E, Oliver A (2014) Antimicrobial susceptibility testing in biofilm growing bacteria. Clin Microbiol Infect 20:981–990CrossRefPubMedGoogle Scholar
  51. Mangoni ML (2006) Temporins, anti-infective peptides with expanding properties. Cell Mol Life Sci 63:1060–1069CrossRefPubMedGoogle Scholar
  52. Mangoni ML (2011) Host-defense peptides: from biology to therapeutic strategies. Cell Mol Life Sci 68:2157–2159CrossRefPubMedGoogle Scholar
  53. Mangoni ML, Carotenuto A, Auriemma L, Saviello MR, Campiglia P, Gomez-Monterrey I, Malfi S, Marcellini L, Barra D, Novellino E, Grieco P (2011) Structure-activity relationship, conformational and biological studies of temporin L analogues. J Med Chem 54:1298–1307CrossRefPubMedGoogle Scholar
  54. Mangoni ML, Marcellini HG, Simmaco M (2007) Biological characterization and modes of action of temporins and bombinins H, multiple forms of short and mildly cationic anti-microbial peptides from amphibian skin. J Pept Sci 13:603–613CrossRefPubMedGoogle Scholar
  55. Mangoni ML, Saugar JM, Dellisanti M, Barra D, Simmaco M, Rivas L (2005) Temporins, small antimicrobial peptides with leishmanicidal activity. J Biol Chem 280:984–990CrossRefPubMedGoogle Scholar
  56. Mangoni ML, Shai Y (2011) Short native antimicrobial peptides and engineered ultrashort lipopeptides: similarities and differences in cell specificities and modes of action. Cell Mol Life Sci 68:2267–2280CrossRefPubMedGoogle Scholar
  57. Mansour SC, Pena OM, Hancock RE (2014) Host defense peptides: front-line immunomodulators. Trends Immunol 35:443–450CrossRefPubMedGoogle Scholar
  58. Manzo G, Casu M, Rinaldi AC, Montaldo NP, Luganini A, Gribaudo G, Scorciapino MA (2014) Folded structure and insertion depth of the frog-skin antimicrobial Peptide esculentin-1b(1-18) in the presence of differently charged membrane-mimicking micelles. J Nat Prod 77:2410–2417CrossRefPubMedGoogle Scholar
  59. Manzo G, Sanna R, Casu M, Mignogna G, Mangoni ML, Rinaldi AC, Scorciapino MA (2012) Toward an improved structural model of the frog-skin antimicrobial peptide esculentin-1b(1-18). Biopolymers 97:873–881CrossRefPubMedGoogle Scholar
  60. Marcellini L, Borro M, Gentile G, Rinaldi AC, Stella L, Aimola P, Barra D, Mangoni ML (2009) Esculentin-1b(1-18)–a membrane-active antimicrobial peptide that synergizes with antibiotics and modifies the expression level of a limited number of proteins in Escherichia coli. FEBS J 276:5647–5664CrossRefPubMedGoogle Scholar
  61. Millar FA, Simmonds NJ, Hodson ME (2009) Trends in pathogens colonising the respiratory tract of adult patients with cystic fibrosis, 1985–2005. J Cyst Fibros 8:386–391CrossRefPubMedGoogle Scholar
  62. Moreau-Marquis S, Stanton BA, O’Toole GA (2008) Pseudomonas aeruginosa biofilm formation in the cystic fibrosis airway. Pulm Pharmacol Ther 21:595–599PubMedCentralCrossRefPubMedGoogle Scholar
  63. Nguyen LT, Chau JK, Perry NA, de Boer L, Zaat SA, Vogel HJ (2010) Serum stabilities of short tryptophan- and arginine-rich antimicrobial peptide analogs. PLoS One 5:e12684PubMedCentralCrossRefPubMedGoogle Scholar
  64. Noto PB, Abbadessa G, Cassone M, Mateo GD, Agelan A, Wade JD, Szabo D, Kocsis B, Nagy K, Rozgonyi F, Otvos L Jr (2008) Alternative stabilities of a proline-rich antibacterial peptide in vitro and in vivo. Protein Sci 17:1249–1255PubMedCentralCrossRefPubMedGoogle Scholar
  65. Oren Z, Hong J, Shai Y (1997) A repertoire of novel antibacterial diastereomeric peptides with selective cytolytic activity. J Biol Chem 272:14643–14649CrossRefPubMedGoogle Scholar
  66. Oren Z, Shai Y (1997) Selective lysis of bacteria but not mammalian cells by diastereomers of melittin: structure-function study. Biochemistry 36:1826–1835CrossRefPubMedGoogle Scholar
  67. Osherov N, Levitzki A (1994) Epidermal-growth-factor-dependent activation of the src-family kinases. Eur J Biochem 225:1047–1053CrossRefPubMedGoogle Scholar
  68. Papo N, Oren Z, Pag U, Sahl HG, Shai Y (2002) The consequence of sequence alteration of an amphipathic alpha-helical antimicrobial peptide and its diastereomers. J Biol Chem 277:33913–33921CrossRefPubMedGoogle Scholar
  69. Peschel A, Otto M, Jack RW, Kalbacher H, Jung G, Gotz F (1999) Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides. J Biol Chem 274:8405–8410CrossRefPubMedGoogle Scholar
  70. Pike LJ, Han X, Gross RW (2005) Epidermal growth factor receptors are localized to lipid rafts that contain a balance of inner and outer leaflet lipids: a shotgun lipidomics study. J Biol Chem 280:26796–26804PubMedCentralCrossRefPubMedGoogle Scholar
  71. Pini A, Falciani C, Mantengoli E, Bindi S, Brunetti J, Iozzi S, Rossolini GM, Bracci L (2010) A novel tetrabranched antimicrobial peptide that neutralizes bacterial lipopolysaccharide and prevents septic shock in vivo. FASEB J 24:1015–1022CrossRefPubMedGoogle Scholar
  72. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088CrossRefPubMedGoogle Scholar
  73. Pouny Y, Rapaport D, Mor A, Nicolas P, Shai Y (1992) Interaction of antimicrobial dermaseptin and its fluorescently labeled analogues with phospholipid membranes. Biochemistry 31:12416–12423CrossRefPubMedGoogle Scholar
  74. Pulido D, Nogues MV, Boix E, Torrent M (2012) Lipopolysaccharide neutralization by antimicrobial peptides: a gambit in the innate host defense strategy. J Innate Immun 4:327–336CrossRefPubMedGoogle Scholar
  75. Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, Ulmer AJ, Zahringer U, Seydel U, Di Padova F et al (1994) Bacterial endotoxin: molecular relationships of structure to activity and function. Faseb J 8:217–225PubMedGoogle Scholar
  76. Rosenfeld Y, Barra D, Simmaco M, Shai Y, Mangoni ML (2006a) A synergism between temporins toward gram-negative bacteria overcomes resistance imposed by the lipopolysaccharide protective layer. J Biol Chem 281:28565–28574CrossRefPubMedGoogle Scholar
  77. Rosenfeld Y, Papo N, Shai Y (2006b) Endotoxin (lipopolysaccharide) neutralization by innate immunity host-defense peptides. Peptide properties and plausible modes of action. J Biol Chem 281:1636–1643CrossRefPubMedGoogle Scholar
  78. Rosenfeld Y, Sahl HG, Shai Y (2008) Parameters involved in antimicrobial and endotoxin detoxification activities of antimicrobial peptides. Biochemistry 47:6468–6478CrossRefPubMedGoogle Scholar
  79. Rosenfeld Y, Shai Y (2006) Lipopolysaccharide (Endotoxin)-host defense antibacterial peptides interactions: role in bacterial resistance and prevention of sepsis. Biochim Biophys Acta 1758:1513–1522CrossRefPubMedGoogle Scholar
  80. Schumann RR, Leong SR, Flaggs GW, Gray PW, Wright SD, Mathison JC, Tobias PS, Ulevitch RJ (1990) Structure and function of lipopolysaccharide binding protein. Science 249:1429–1431CrossRefPubMedGoogle Scholar
  81. Semple F, Dorin JR (2012) beta-Defensins: multifunctional modulators of infection, inflammation and more? J Innate Immun 4:337–348CrossRefPubMedGoogle Scholar
  82. Shai Y (2002) Mode of action of membrane active antimicrobial peptides. Biopolymers 66:236–248CrossRefPubMedGoogle Scholar
  83. Shai Y, Oren Z (1996) Diastereoisomers of cytolysins, a novel class of potent antibacterial peptides. J Biol Chem 271:7305–7308CrossRefPubMedGoogle Scholar
  84. Strahilevitz J, Mor A, Nicolas P, Shai Y (1994) Spectrum of antimicrobial activity and assembly of dermaseptin-b and its precursor form in phospholipid membranes. Biochemistry 33:10951–10960CrossRefPubMedGoogle Scholar
  85. Takayama K, Mitchell DH, Din ZZ, Mukerjee P, Li C, Coleman DL (1994) Monomeric Re lipopolysaccharide from Escherichia coli is more active than the aggregated form in the Limulus amebocyte lysate assay and in inducing Egr-1 mRNA in murine peritoneal macrophages. J Biol Chem 269:2241–2244PubMedGoogle Scholar
  86. Tobias PS, Ulevitch RJ (1993) Lipopolysaccharide binding protein and CD14 in LPS dependent macrophage activation. Immunobiology 187:227–232CrossRefPubMedGoogle Scholar
  87. Tokumaru S, Sayama K, Shirakata Y, Komatsuzawa H, Ouhara K, Hanakawa Y, Yahata Y, Dai X, Tohyama M, Nagai H, Yang L, Higashiyama S, Yoshimura A, Sugai M, Hashimoto K (2005) Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37. J Immunol 175:4662–4668CrossRefPubMedGoogle Scholar
  88. Uccelletti D, Zanni E, Marcellini L, Palleschi C, Barra D, Mangoni ML (2010) Anti-Pseudomonas activity of frog skin antimicrobial peptides in a Caenorhabditis elegans infection model: a plausible mode of action in vitro and in vivo. Antimicrob Agents Chemother 54:3853–3860PubMedCentralCrossRefPubMedGoogle Scholar
  89. Wang YW, Ren JH, Xia K, Wang SH, Yin TF, Xie DH, Li LH (2012) Effect of mitomycin on normal dermal fibroblast and HaCat cell: an in vitro study. J Zhejiang Univ Sci B 13:997–1005PubMedCentralCrossRefPubMedGoogle Scholar
  90. Xiong YQ, Hady WA, Deslandes A, Rey A, Fraisse L, Kristensen HH, Yeaman MR, Bayer AS (2011) Efficacy of NZ2114, a novel plectasin-derived cationic antimicrobial peptide antibiotic, in experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 55:5325–5330PubMedCentralCrossRefPubMedGoogle Scholar
  91. Yeung AT, Gellatly SL, Hancock RE (2011) Multifunctional cationic host defence peptides and their clinical applications. Cell Mol Life Sci 68:2161–2176CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Antonio Di Grazia
    • 1
  • Floriana Cappiello
    • 1
  • Hadar Cohen
    • 2
  • Bruno Casciaro
    • 1
  • Vincenzo Luca
    • 1
  • Alessandro Pini
    • 3
  • Y. Peter Di
    • 4
  • Yechiel Shai
    • 2
  • Maria Luisa Mangoni
    • 1
    Email author
  1. 1.Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biochemical SciencesSapienza University of RomeRomeItaly
  2. 2.Department of Biological ChemistryThe Weizmann Institute of ScienceRehovotIsrael
  3. 3.Department of Medical BiotechnologyUniversity of SienaSienaItaly
  4. 4.Department of Environmental and Occupational HealthUniversity of PittsburghPittsburghUSA

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