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Thermodynamic Analysis of the Lipopolysaccharide-Dependent Resistance of Gram-Negative Bacteria against Polymyxin B

Jörg Howe ^*, Jörg Andrä ^*, Raquel Conde , Maite Iriarte , Patrick Garidel , Michel H. J. Koch , Thomas Gutsmann ^*, Ignacio Moriyón  and Klaus Brandenburg ^*

^* Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, D-23845 Borstel, Germany; Universidad de Navarra, Departmento de Microbiologia, E-31008 Pamplona, Spain; Institut für Physikalische Chemie, Martin-Luther-Universität Halle-Wittenberg, D-06108 Halle, Germany; and European Molecular Biology Laboratory c/o DESY, D-22603 Hamburg, Germany

Correspondence: Address reprint requests to Klaus Brandenburg, Forschungszentrum Borstel, Div. of Biophysics Parkallee 10, D-23845 Borstel, Germany. Tel.: 49-(0)4537-188235; Fax: 49-(0)4537-188632; E-mail: Kbranden{at}fz-borstel.de.

Cationic antimicrobial cationic peptides (CAMP) have been found in recent years to play a decisive role in hosts' defense against microbial infection. They have also been investigated as a new therapeutic tool, necessary in particular due to the increasing resistance of microbiological populations to antibiotics. The structural basis of the activity of CAMPs has only partly been elucidated and may comprise quite different mechanism at the site of the bacterial cell membranes or in their cytoplasm. Polymyxin B (PMB) is a CAMP which is effective in particular against Gram-negative bacteria and has been well studied with the aim to understand its interaction with the outer membrane or isolated membrane components such as lipopolysaccharide (LPS) and to define the mechanism by which the peptides kill bacteria or neutralize LPS. Since PMB resistance of bacteria is a long-known phenomenon and is attributed to structural changes in the LPS moiety of the respective bacteria, we have performed a thermodynamic and biophysical analysis to get insights into the mechanisms of various LPS/PMB interactions in comparison to LPS from sensitive strains. In isothermal titration calorimetric (ITC) experiments considerable differences of PMB binding to sensitive and resistant LPS were found. For sensitive LPS the endothermic enthalpy change in the gel phase of the hydrocarbon chains converts into an exothermic reaction in the liquid crystalline phase. In contrast, for resistant LPS the binding enthalpy change remains endothermic in both phases. As infrared data show, these differences can be explained by steric changes in the headgroup region of the respective LPS.

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