New antiseptic peptides to protect against endotoxin-mediated shock.
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.
Gutsmann
Thomas
T
Forschungszentrum Borstel, Division of Biophysics, Parkallee 10, D-23845 Borstel, Germany.
Razquin-Olazarán
Iosu
I
Kowalski
Ina
I
Kaconis
Yani
Y
Howe
Jörg
J
Bartels
Rainer
R
Hornef
Mathias
M
Schürholz
Tobias
T
Rössle
Manfred
M
Sanchez-Gómez
Susana
S
Moriyon
Ignacio
I
Martinez de Tejada
Guillermo
G
Brandenburg
Klaus
K
D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D001419:Bacteria / Q000187:drug effects; D002151:Calorimetry; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000737:chemistry / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D012772:Shock, Septic / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*
D000890:Anti-Infective Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D010455:Peptides