Antibacterial peptide acylation, which mimics the structure of the natural lipopeptide polymyxin B, increases antimicrobial and endotoxin-neutralizing activities. The interaction of the lactoferricin-derived peptide LF11 and its N-terminally acylated analogue, lauryl-LF11, with different chemotypes of bacterial lipopolysaccharide (LPS Re, Ra and smooth S form) was investigated by biophysical means and was related to the peptides' biological activities. Both peptides exhibit high antibacterial activity against the three strains of Salmonella enterica differing in the LPS chemotype. Lauryl-LF11 has one order of magnitude higher activity against Re-type, but activity against Ra- and S-type bacteria is comparable with that of LF11. The alkyl derivative peptide lauryl-LF11 shows a much stronger inhibition of the LPS-induced cytokine induction in human mononuclear cells than LF11. Although peptide–LPS interaction is essentially of electrostatic nature, the lauryl-modified peptide displays a strong hydrophobic component. Such a feature might then explain the fact that saturation of the peptide binding takes place at a much lower peptide/LPS ratio for LF11 than for lauryl-LF11, and that an overcompensation of the negative LPS backbone charges is observed for lauryl-LF11. The influence of LF11 on the gel-to-liquid-crystalline phase-transition of LPS is negligible for LPS Re, but clearly fluidizing for LPS Ra. In contrast, lauryl-LF11 causes a cholesterol-like effect in the two chemotypes, fluidizing in the gel and rigidifying of the hydrocarbon chains in the liquid-crystalline phase. Both peptides convert the mixed unilamellar/non-lamellar aggregate structure of lipid A, the ‘endotoxic principle’ of LPS, into a multilamellar one. These data contribute to the understanding of the mechanisms of the peptide-mediated neutralization of endotoxin and effect of lipid modification of peptides.
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Research Article|
December 14 2004
Enhancement of endotoxin neutralization by coupling of a C12-alkyl chain to a lactoferricin-derived peptide
Jörg ANDRÄ;
Jörg ANDRÄ
1
*Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Division of Biophysics, Parkallee 10, D-23845 Borstel, Germany
1To whom correspondence should be addressed (email jandrae@fz-borstel.de).
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Karl LOHNER;
Karl LOHNER
†Österreichische Akademie der Wissenschaften, Institut für Biophysik und Röntgenstrukturforschung, Schmiedlstrasse 6, A-8042 Graz, Austria
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Sylvie E. BLONDELLE;
Sylvie E. BLONDELLE
‡Torrey Pines Institute for Molecular Studies, Department of Biochemistry/Microbiology, 3550 General Atomics Court, San Diego, CA 92121, U.S.A.
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Roman JERALA;
Roman JERALA
§National Institute of Chemistry, Hajdrihova 19, 1000 SL-Ljubljana, Slovenia
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Ignacio MORIYON;
Ignacio MORIYON
∥Universidad de Navarra, Departamento de Microbiologia, Irunlarrea 1, 31008 Pamplona, Spain
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Michel H. J. KOCH;
Michel H. J. KOCH
¶European Molecular Biology Laboratory, EMBL c/o DESY, Hamburg outstation, Notkestrasse 85, D-22603 Hamburg, Germany
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Patrick GARIDEL;
Patrick GARIDEL
**Martin-Luther-Universität Halle/Wittenberg, Institut für Physikalische Chemie, Mühlpforte 1, D-06108 Halle/Saale, Germany
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Klaus BRANDENBURG
Klaus BRANDENBURG
*Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Division of Biophysics, Parkallee 10, D-23845 Borstel, Germany
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Publisher: Portland Press Ltd
Received:
July 27 2004
Revision Received:
August 27 2004
Accepted:
September 02 2004
Accepted Manuscript online:
September 02 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 385 (1): 135–143.
Article history
Received:
July 27 2004
Revision Received:
August 27 2004
Accepted:
September 02 2004
Accepted Manuscript online:
September 02 2004
Citation
Jörg ANDRÄ, Karl LOHNER, Sylvie E. BLONDELLE, Roman JERALA, Ignacio MORIYON, Michel H. J. KOCH, Patrick GARIDEL, Klaus BRANDENBURG; Enhancement of endotoxin neutralization by coupling of a C12-alkyl chain to a lactoferricin-derived peptide. Biochem J 1 January 2005; 385 (1): 135–143. doi: https://doi.org/10.1042/BJ20041270
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