Synthetic Anti-lipopolysaccharide Peptides (SALPs) as Effective Inhibitors of Pathogen-Associated Molecular Patterns (PAMPs)

  • Wilmar Correa
  • Lena Heinbockel
  • Guillermo Martinez-de-Tejada
  • Susana Sánchez
  • Patrick Garidel
  • Tobias Schürholz
  • Walter Mier
  • Aline Dupont
  • Mathias Hornef
  • Thomas Gutsmann
  • Karl Mauss
  • Günther Weindl
  • Klaus BrandenburgEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1117)


Antimicrobial peptides (AMPs) are in the focus of scientific research since the 1990s. In most cases, the main aim was laid on the design of AMP to kill bacteria effectively, with particular emphasis on broadband action and independency on antibiotic resistance. However, so far no approved drug on the basis of AMP has entered the market.

Our approach of constructing AMP, called synthetic anti-lipopolysaccharide peptides (SALPs), on the basis of inhibiting the inflammatory action of lipopolysaccharide (LPS, endotoxin) from Gram-negative bacteria was focused on the neutralization of the decisive toxins. These are, beside LPS from Gram-negative bacteria, the lipoproteins (LP) from Gram-positive origin. Although some of the SALPs have an antibacterial action, the most important property is the high-affinity binding to LPS and LP, whether as constituent of the bacteria or in free form which prevents the damaging inflammation, that could otherwise lead to life-threatening septic shock. Most importantly, the SALP may inhibit inflammation independently of the resistance status of the bacteria, and so far the repeated use of the peptides apparently does not cause resistance of the attacking pathogens.

In this chapter, an overview is given over the variety of possible applications in the field of fighting against severe bacterial infections, from the use in systemic infection/inflammation up to various topical applications such as anti-biofilm action and severe skin and soft tissue infections.


  1. Andrä J, Lamata M, Martinez de Tejada G, Bartels R, Koch MHJ, Brandenburg K (2004) Cyclic antimicrobial peptides based on Limulus anti lipopolysaccharide factor for neutralization of lipopolysaccharide. Biochem Pharmacol 68(7):1297–1307. CrossRefPubMedGoogle Scholar
  2. Andrä J, Lohner K, Blondelle SE, Jerala R, Moriyon I, Koch MH, Garidel P, Brandenburg K (2005) Enhancement of endotoxin neutralization by coupling of a C12-alkyl chain to a lactoferricin-derived peptide. Biochem J 385(Pt 1):135–143. CrossRefPubMedGoogle Scholar
  3. Andrä J, Gutsmann T, Garidel P, Brandenburg K (2006) Mechanisms of endotoxin neutralization by synthetic cationic compounds. J Endotoxin Res 12(5):261–277. CrossRefPubMedGoogle Scholar
  4. Andrä J, Howe J, Garidel P, Rössle M, Richter W, Leiva-Leon J, Moriyon I, Bartels R, Gutsmann T, Brandenburg K (2007) Mechanism of interaction of optimized limulus derived cyclic peptides with endotoxins: thermodynamic, biophysical and microbiological analysis. Biochem J 406(2):297–307. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Barcena-Varela S, Martinez de Tejada G, Martin L, Schuerholz T, Gil-Royo AG, Fukuoka S, Goldmann T, Droemann D, Correa W, Gutsmann T, Brandenburg K, Heinbockel L (2017) Coupling killing to neutralization: combined therapy with ceftriaxone/Pep19-2.5 counteracts sepsis in rabbits. Exp Mol Med 49(6):e345. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Boto A, Perez de la Lastra JM, Gonzalez CC (2018) The road from host-defense peptides to a new generation of antimicrobial drugs. Molecules 23(2). CrossRefGoogle Scholar
  7. Brandenburg K, Andrä J, Müller M, Koch MHJ, Garidel P (2003) Physicochemical properties of bacterial glycopolymers in relation to bioactivity. Carbohydr Res 338(23):2477–2489. CrossRefPubMedGoogle Scholar
  8. Brandenburg K, David A, Howe J, Koch MHJ, Andrä J, Garidel P (2005) Temperature dependence of the binding of endotoxins to the polycationic peptides polymyxin B and its nonapeptide. Biophys J 88(3):1845–1858. CrossRefPubMedGoogle Scholar
  9. Brandenburg K, Garidel P, Fukuoka S, Howe J, Koch MHJ, Gutsmann T, Andrä J (2010) Molecular basis for endotoxin neutralization by amphipathic peptides derived from the alpha helical cationic core region of NK lysin. Biophys Chem 150(1–3):80–87. CrossRefPubMedGoogle Scholar
  10. Brandenburg K, Howe J, Sanchez-Gomez S, Garidel P, Roessle M, Andrä J, Jerala R, Zweytick D, Lohner K, Rappolt M, Blondelle S, Moriyon I, Martinez de Tejada GM (2010b) Effective antimicrobial and anti-endotoxin activity of cationic peptides based on lactoferricin: a biophysical and microbiological study. Anti-Infect Agents Med Chem 9(1):9–22. CrossRefGoogle Scholar
  11. Brandenburg K, Andrä J, Garidel P, Gutsmann T (2011) Peptide- based treatment of sepsis. Appl Microbiol Biotechol 90(3):799–808. CrossRefGoogle Scholar
  12. Brandenburg K, Heinbockel L, Correa W, Lohner K (2016) Peptides with dual mode of action: killing bacteria and preventing endotoxin-induced sepsis. Biochim Biophys Acta 1858(5):971–979. CrossRefPubMedGoogle Scholar
  13. Dupont A, Heinbockel L, Brandenburg K, Hornef MW (2014) Antimicrobial peptides and the enteric mucus layer act in concert to protect the intestinal mucosa. Gut Microbes 5(6):761–765. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Dupont A, Kaconis Y, Yang I, Albers T, Woltemate S, Heinbockel L, Andersson M, Suerbaum S, Brandenburg K, Hornef MW (2015) Intestinal mucus affinity and biological activity of an orally administered antibacterial and anti-inflammatory peptide. Gut 64(2):222–232. CrossRefPubMedGoogle Scholar
  15. Ferrari D, Pizzirani C, Adinolfi E, Forchap S, Sitta B, Turchet L, Falzoni S, Minelli M, Baricordi R, Di Virgilio F (2004) The antibiotic polymyxin B modulates P2X7 receptor function. J Immunol 173(7):4652–4660. CrossRefPubMedGoogle Scholar
  16. Fink MP, Warren HS (2014) Strategies to improve drug development for sepsis. Nat Rev Drug Discov 13:741. CrossRefPubMedGoogle Scholar
  17. Fox JL (2013) Antimicrobial peptides stage a comeback. Nat Biotechnol 31:379. CrossRefPubMedGoogle Scholar
  18. Frykberg RG, Banks J (2015) Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle) 4(9):560–582. CrossRefGoogle Scholar
  19. Garidel P, Brandenburg K (2009) Current understanding of polymyxin B applications in bacteraemia/sepsis therapy prevention: clinical, pharmaceutical, structural and mechanistic aspects. Antinfect Agents Med Chem 8(4):367–385CrossRefGoogle Scholar
  20. Garidel P, Andrä J, Howe J, Gutsmann T, Brandenburg K (2007) Novel antiinflammatory and antiinfective agents. Anti-infect Agents Med Chem 6(3):185–200. CrossRefGoogle Scholar
  21. Gutsmann T, Razquin-Olazaran I, Kowalski I, Kaconis Y, Howe J, Bartels R, Hornef M, Schürholz T, Rössle M, Sanchez-Gomez S, Moriyon I, Martinez de Tejada G, Brandenburg K (2010) New antiseptic peptides to protect against endotoxin-mediated shock. Antimicrob Agents Chemother 54(9):3817–3824. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Habersetzer F, Leboeuf C, Doffoël M, Zeisel MB, Baumert TF (2013) Synthetic anti-lipopolysaccharide peptides and hepatitis C virus infection. Exp Opin Invest Drugs 22(7):853–862. CrossRefGoogle Scholar
  23. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA (2013) Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341(6151):1250–1253. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Heinbockel L, Sanchez-Gomez S, Martinez de Tejada G, Dömming S, Brandenburg J, Kaconis Y, Hornef M, Dupont A, Marwitz S, Goldmann T, Ernst M, Gutsmann T, Schürholz T, Brandenburg K (2013) Preclinical investigations reveal the broad-spectrum neutralizing activity of peptide Pep19-2.5 on bacterial pathogenicity factors. Antimicrob Agents Chemother 57(3):1480–1487. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Heinbockel L, Marwitz S, Barcena Varela S, Ferrer-Espada R, Reiling N, Goldmann T, Gutsmann T, Mier W, Schürholz T, Drömann D, Brandenburg K, Martinez de Tejada G (2015) Therapeutical administration of peptide Pep19-2.5 and ibuprofen reduces inflammation and prevents lethal sepsis. PLoS One 10(7):e0133291. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Hilchie AL, Wuerth K, Hancock RE (2013) Immune modulation by multifaceted cationic host defense (antimicrobial) peptides. Nat Chem Biol 9(12):761–768. CrossRefPubMedGoogle Scholar
  27. Howe J, Andrä J, Conde R, Iriarte M, Garidel P, Koch MHJ, Gutsmann T, Moriyon I, Brandenburg K (2007) Thermodynamic analysis of the lipopolysaccharide dependent resistance of gram-negative bacteria against polymyxin B. Biophys J 92(8):2796–2805. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kaconis Y, Kowalski I, Howe J, Brauser A, Richter W, Razquin-Olazaran I, Inigo-Pestana M, Garidel P, Rössle M, Martinez de Tejada G, Gutsmann T, Brandenburg K (2011) Biophysical mechanisms of endotoxin neutralization by cationic amphiphilic peptides. Biophys J 100(11):2652–2661. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Katarzyna EG, Małgorzata D (2017) Antimicrobial peptides under clinical trials. Curr Top Med Chem 17(5):620–628. CrossRefGoogle Scholar
  30. Khare S, Dorfleutner A, Bryan NB, Yun C, Radian AD, de Almeida L, Rojanasakul Y, Stehlik C (2012) An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 36(3):464–476. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Krepstakies M, Lucifora J, Nagel CH, Zeisel MB, Holstermann B, Hohenberg H, Kowalski I, Gutsmann T, Baumert TF, Brandenburg K, Hauber J, Protzer U (2012) A new class of synthetic peptide inhibitors blocks attachment and entry of human pathogenic viruses. J Infect Dis 205(11):1654–1664. CrossRefPubMedGoogle Scholar
  32. Kuhlmann N, Heinbockel L, Correa W, Gutsmann T, Goldmann T, Englisch U, Brandenburg K (2018) Peptide drug stability: the anti-inflammatory drugs Pep19-2.5 and Pep19-4LF in cream formulation. Eur J Pharm Sci 115:240–247. CrossRefPubMedGoogle Scholar
  33. Mangoni ML, McDermott AM, Zasloff M (2016) Antimicrobial peptides and wound healing: biological and therapeutic considerations. Exp Dermatol 25(3):167–173. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Martin L, De Santis R, Koczera P, Simons N, Haase H, Heinbockel L, Brandenburg K, Marx G, Schuerholz T (2015) The synthetic antimicrobial peptide 19-2.5 interacts with heparanase and heparan sulfate in murine and human sepsis. PLoS One 10(11):e0143583. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Martin L, Horst K, Chiazza F, Oggero S, Collino M, Brandenburg K, Hildebrand F, Marx G, Thiemermann C, Schuerholz T (2016) The synthetic antimicrobial peptide 19-2.5 attenuates septic cardiomyopathy and prevents down-regulation of SERCA2 in polymicrobial sepsis. Sci Rep 6:37277. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Martínez de Tejada GM, Sanchez-Gomez S, Razquin-Olazaran I, Kowalski I, Kaconis Y, Heinbockel L, Andrä J, Schürholz T, Hornef M, Dupont A, Garidel P, Lohner K, Gutsmann T, David SA, Brandenburg K (2012) Bacterial cell wall compounds as promising targets of antimicrobial agents I. Antimicrobial Peptides and Lipopolyamines. Curr Drug Targets 13(9):1121–1130CrossRefGoogle Scholar
  37. Martinez de Tejada G, Heinbockel L, Ferrer-Espada R, Heine H, Alexander C, Barcena-Varela S, Goldmann T, Correa W, Wiesmüller KH, Gisch N, Sanchez-Gomez S, Fukuoka S, Schürholz T, Gutsmann T, Brandenburg K (2015) Lipoproteins/peptides are sepsis-inducing toxins from bacteria that can be neutralized by synthetic anti-endotoxin peptides. Sci Rep 5:14292. CrossRefPubMedGoogle Scholar
  38. Mirski T, Niemcewicz M, Bartoszcze M, Gryko R, Michalski A (2017) Utilisation of peptides against microbial infections – a review. Ann Agric Environ Med 25(2):205–210. CrossRefPubMedGoogle Scholar
  39. Mishra B, Reiling S, Zarena D, Wang G (2017) Host defense antimicrobial peptides as antibiotics: design and application strategies. Curr Opin Chem Biol 38:87–96. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Molchanova N, Hansen PR, Franzyk H (2017) Advances in development of antimicrobial peptidomimetics as potential drugs. Molecules 22(9).
  41. Nordström R, Malmsten M (2017) Delivery systems for antimicrobial peptides. Adv Colloid Interf Sci 242:17–34. CrossRefGoogle Scholar
  42. Opal SM, Laterre P, Francois B et al (2013) Effect of eritoran, an antagonist of md2-tlr4, on mortality in patients with severe sepsis: the access randomized trial. JAMA 309(11):1154–1162. CrossRefPubMedGoogle Scholar
  43. Park KS, Choi KH, Kim YS, Hong BS, Kim OY, Kim JH, Yoon CM, Koh GY, Kim YK, Gho YS (2010) Outer membrane vesicles derived from Escherichia coli induce systemic inflammatory response syndrome. PLoS One 5(6):e11334. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Pfalzgraff A, Heinbockel L, Su Q, Gutsmann T, Brandenburg K, Weindl G (2016) Synthetic antimicrobial and LPS-neutralising peptides suppress inflammatory and immune responses in skin cells and promote keratinocyte migration. Sci Rep 6:31577. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Pfalzgraff A, Heinbockel L, Su Q, Brandenburg K, Weindl G (2017) Synthetic anti-endotoxin peptides inhibit cytoplasmic LPS-mediated responses. Biochem Pharmacol 140:64–72. CrossRefPubMedGoogle Scholar
  46. Pfalzgraff A, Barcena-Varela S, Heinbockel L, Gutsmann T, Brandenburg K, Martinez de Tejada G, Weindl G (2018a) Antimicrobial endotoxin-neutralizing peptides promote keratinocyte migration via P2X7 receptor activation and accelerate wound healing in vivo. Br J Pharmacol. CrossRefGoogle Scholar
  47. Pfalzgraff A, Brandenburg K, Weindl G (2018b) Antimicrobial peptides and their therapeutic potential for bacterial skin infections and wounds. Front Pharmacol 9:281. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Rice TW, Wheeler AP, Bernard GR, Vincent JL, Angus DC, Aikawa N, Demeyer I, Sainati S, Amlot N, Cao C, Ii M, Matsuda H, Mouri K, Cohen J (2010) A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med 38(8):1685–1694. CrossRefPubMedGoogle Scholar
  49. Schuerholz T, Doemming S, Hornef M, Martin L, Simon TP, Heinbockel L, Brandenburg K, Marx G (2013) The anti inflammatory effect of the synthetic antimicrobial peptide 19-2.5 in a murine sepsis model: a prospective randomized study. Crit Care 17(1):R3. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Serra R, Grande R, Butrico L, Rossi A, Settimio UF, Caroleo B, Amato B, Gallelli L, de Franciscis S (2015) Chronic wound infections: the role of Pseudomonas aeruginosa and Staphylococcus aureus. Expert Rev Anti-Infect Ther 13(5):605–613. CrossRefPubMedGoogle Scholar
  51. Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L, Shao F (2014) Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514(7521):187–192. CrossRefPubMedGoogle Scholar
  52. Sierra JM, Fusté E, Rabanal F, Vinuesa T, Viñas M (2017) An overview of antimicrobial peptides and the latest advances in their development. Expert Opin Biol Ther 17(6):663–676. CrossRefPubMedGoogle Scholar
  53. Sil D, Heinbockel L, Kaconis Y, Rössle M, Garidel P, Gutsmann T, David SA, Brandenburg K (2013) Biophysical mechanisms of the neutralization of endotoxins by lipopolyamines. Open Biochem J 7:82–93. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Tabah A, Koulenti D, Laupland K, Misset B, Valles J, Bruzzi de Carvalho F, Paiva JA, Cakar N, Ma X, Eggimann P, Antonelli M, Bonten MJ, Csomos A, Krueger WA, Mikstacki A, Lipman J, Depuydt P, Vesin A, Garrouste-Orgeas M, Zahar JR, Blot S, Carlet J, Brun-Buisson C, Martin C, Rello J, Dimopoulos G, Timsit JF (2012) Characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the EUROBACT international cohort study. Intensive Care Med 38(12):1930–1945. CrossRefPubMedGoogle Scholar
  55. Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, Pulcini C, Kahlmeter G, Kluytmans J, Carmeli Y, Ouellette M, Outterson K, Patel J, Cavaleri M, Cox EM, Houchens CR, Grayson ML, Hansen P, Singh N, Theuretzbacher U, Magrini N, Aboderin AO, Al-Abri SS, Awang Jalil N, Benzonana N, Bhattacharya S, Brink AJ, Burkert FR, Cars O, Cornaglia G, Dyar OJ, Friedrich AW, Gales AC, Gandra S, Giske CG, Goff DA, Goossens H, Gottlieb T, Guzman Blanco M, Hryniewicz W, Kattula D, Jinks T, Kanj SS, Kerr L, Kieny M-P, Kim YS, Kozlov RS, Labarca J, Laxminarayan R, Leder K, Leibovici L, Levy-Hara G, Littman J, Malhotra-Kumar S, Manchanda V, Moja L, Ndoye B, Pan A, Paterson DL, Paul M, Qiu H, Ramon-Pardo P, Rodríguez-Baño J, Sanguinetti M, Sengupta S, Sharland M, Si-Mehand M, Silver LL, Song W, Steinbakk M, Thomsen J, Thwaites GE, van der Meer JWM, Van Kinh N, Vega S, Villegas MV, Wechsler-Fördös A, Wertheim HFL, Wesangula E, Woodford N, Yilmaz FO, Zorzet A (2018) Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 18(3):318–327. CrossRefPubMedGoogle Scholar
  56. Vanaja SK, Russo AJ, Behl B, Banerjee I, Yankova M, Deshmukh SD, Rathinam VA (2016) Bacterial outer membrane vesicles mediate cytosolic localization of LPS and caspase-11 activation. Cell 165(5):1106–1119. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83(3):835–870. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Wilmar Correa
    • 1
  • Lena Heinbockel
    • 2
  • Guillermo Martinez-de-Tejada
    • 3
  • Susana Sánchez
    • 3
  • Patrick Garidel
    • 4
  • Tobias Schürholz
    • 5
  • Walter Mier
    • 6
  • Aline Dupont
    • 7
  • Mathias Hornef
    • 7
  • Thomas Gutsmann
    • 1
  • Karl Mauss
    • 8
  • Günther Weindl
    • 9
  • Klaus Brandenburg
    • 10
    Email author
  1. 1.LG BiophysikForschungszentrum Borstel, Leibniz LungenzentrumBorstelGermany
  2. 2.Forschungszentrum Borstel, Leibniz LungenzentrumKlinische und Experimentelle PathologieBorstelGermany
  3. 3.Dep. de MicrobiologiaUniversidad de NavarraPamplonaSpain
  4. 4.Universität Halle-WittenbergHalle/SaaleGermany
  5. 5.Klinik&Poliklinik für Anästhesiologie und IntensivtherapieUniversitätsmedizin RostockRostockGermany
  6. 6.Radiopharmazeutische ChemieUniversitätsklinikum HeidelbergHeidelbergGermany
  7. 7.Universitätsklinik AachenInstitute of Medical MicrobiologyAachenGermany
  8. 8.Asklepios-Klinik Hamburg-AltonaHamburgGermany
  9. 9.Freie Universität Berlin, Institut für PharmazieBerlinGermany
  10. 10.Brandenburg Antiinfektiva GmbH, c/o Forschungszentrum BorstelBorstelGermany

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