title: Enhancement of endotoxin neutralization by coupling of a C12-alkyl chain to a lactoferricin-derived peptide.
abstract: 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.
authors.affiliation: Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Division of Biophysics, Parkallee 10, D-23845 Borstel, Germany. jandrae@fz-borstel.de
authors.forename: Jörg
authors.initials: J
authors.lastname: Andrä
authors.forename: Karl
authors.initials: K
authors.lastname: Lohner
authors.forename: Sylvie E
authors.initials: SE
authors.lastname: Blondelle
authors.forename: Roman
authors.initials: R
authors.lastname: Jerala
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moriyon
authors.forename: Michel H J
authors.initials: MH
authors.lastname: Koch
authors.forename: Patrick
authors.initials: P
authors.lastname: Garidel
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
mesh_terms: D000478:Alkylation; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002152:Calorimetry, Differential Scanning; D002412:Cations / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007781:Lactoferrin / Q000737:chemistry*; D007963:Leukocytes, Mononuclear; D008555:Melitten / Q000138:chemical synthesis / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019779:Salmonella enterica; D017550:Spectroscopy, Fourier Transform Infrared; D055672:Static Electricity; D013696:Temperature; D013816:Thermodynamics; D014961:X-Ray Diffraction
chemical_list: D000900:Anti-Bacterial Agents; D002412:Cations; D004731:Endotoxins; D010455:Peptides; C082171:lactoferricin B; D008555:Melitten; D007781:Lactoferrin; D002118:Calcium