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Temperature Dependence of the Binding of Endotoxins to the Polycationic Peptides Polymyxin B and Its Nonapeptide

Klaus Brandenburg ^*, Alexander David ^*, Jörg Howe ^*, Michel H. J. Koch , Jörg Andrä ^* and Patrick Garidel 

^* Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, D-23845 Borstel, Germany; European Molecular Biology Laboratory, Deutsches Elektronen-Synchrotron, D-22603 Hamburg, Germany; and Martin-Luther-Universität Halle/Wittenberg, Institut für Physikalische Chemie, D-06108 Halle/Saale, Germany

Correspondence: Address reprint requests to Dr. Klaus Brandenburg, Forschungszentrum Borstel, LG Biophysik Parkallee 10, D-23845 Borstel, Germany. Tel.: 49-04537-188235; Fax: 49-04537-188632; E-mail: kbranden{at}fz-borstel.de.

The interaction between endotoxins—free lipid A and various lipopolysaccharide (LPS) chemotypes with different sugar chain lengths—and the polycationic peptides polymyxin B and polymyxin nonapeptide has been investigated by isothermal titration calorimetry between 20 and 50°C. The results show a strong dependence of the titration curves on the phase state of the endotoxins. In the gel phase (<30°C for LPS and <45°C for lipid A), an endothermic reaction is observed, for which the driving force is an entropically driven endotoxin-polymyxin interaction, due to disruption of the ordered water structure and cation assembly in the lipid A backbone and adjacent molecules. In the liquid crystalline phase (>35°C for LPS and >47°C for lipid A) an exothermic reaction takes place, which is mainly due to the strong electrostatic interaction of the polymyxins with the negative charges of the endotoxins, i.e., the entropic change S is much lower than in the gel phase. For endotoxins with short sugar chains (lipid A, LPS Re, LPS Rc) the stoichiometry of the polymyxin binding corresponds to pure charge neutralization; for the compounds with longer sugar chains (LPS Ra, LPS S-form) this is no longer valid. This can be related to the lower susceptibility of the corresponding bacterial strains to antibiotics.

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