New Antiseptic Peptides To Protect against Endotoxin-Mediated Shock
- 1 September 2010
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 54 (9), 3817-3824
- https://doi.org/10.1128/aac.00534-10
Abstract
Systemic bacterial infections are associated with high mortality. The access of bacteria or constituents thereof to systemic circulation induces the massive release of immunomodulatory mediators, ultimately causing tissue hypoperfusion and multiple-organ failure despite adequate antibiotic treatment. Lipid A, the “endotoxic principle” of bacterial lipopolysaccharide (LPS), is one of the major bacterial immunostimuli. Here we demonstrate the biological efficacy of rationally designed new synthetic antilipopolysaccharide peptides (SALPs) based on the Limulus anti-LPS factor for systemic application. We show efficient inhibition of LPS-induced cytokine release and protection from lethal septic shock in vivo , whereas cytotoxicity was not observed under physiologically relevant conditions and concentrations. The molecular mechanism of LPS neutralization was elucidated by biophysical techniques. The lipid A part of LPS is converted from its “endotoxic conformation,” the cubic aggregate structure, into an inactive multilamellar structure, and the binding affinity of the peptide to LPS exceeds those of known LPS-binding proteins, such as LPS-binding protein (LBP). Our results thus delineate a novel therapeutic strategy for the clinical management of patients with septic shock.Keywords
This publication has 28 references indexed in Scilit:
- Parameters Involved in Antimicrobial and Endotoxin Detoxification Activities of Antimicrobial PeptidesBiochemistry, 2008
- Biophysical analysis of the interaction of granulysin-derived peptides with enterobacterial endotoxinsBiochimica et Biophysica Acta (BBA) - Biomembranes, 2007
- Mechanism of interaction of optimized Limulus-derived cyclic peptides with endotoxins: thermodynamic, biophysical and microbiological analysisBiochemical Journal, 2007
- Upgrade of the small-angle X-ray scattering beamline X33 at the European Molecular Biology Laboratory, HamburgJournal of Applied Crystallography, 2007
- Mechanisms of endotoxin neutralization by synthetic cationic compoundsInnate Immunity, 2006
- Determination of the Antibacterial and Lipopolysaccharide-Neutralizing Regions of Guinea Pig Neutrophil Cathelicidin Peptide CAP11Antimicrobial Agents and Chemotherapy, 2006
- Enhancement of endotoxin neutralization by coupling of a C12-alkyl chain to a lactoferricin-derived peptideBiochemical Journal, 2004
- Biophysical Characterization of Endotoxin Inactivation by NK-2, an Antimicrobial Peptide Derived from Mammalian NK-LysinAntimicrobial Agents and Chemotherapy, 2004
- Differential effects of α‐, β‐ and γ‐cyclodextrins on human erythrocytesJBIC Journal of Biological Inorganic Chemistry, 1989
- A New Method for the Extraction of R LipopolysaccharidesJBIC Journal of Biological Inorganic Chemistry, 1969