New antiseptic peptides to protect against endotoxin-mediated shock
Palabras clave : 
Antimicrobial peptide
Escherichia coli
In vitro
Lipid A
Lipopolysaccharide
Neutralization
Sepsis
Detoxification
Antibacterial
Binding
Fecha de publicación: 
2010
Editorial : 
American Society for Microbiology
ISSN: 
0066-4804
Cita: 
Gutsmann T, Razquin-Olazaran I, Kowalski I, Kaconis Y, Howe J, Bartels R, et al. New antiseptic peptides to protect against endotoxin-mediated shock. Antimicrob Agents Chemother 2010 Sep;54(9):3817-3824.
Resumen
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.

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