Magainin 2 and PGLa are cationic, amphipathic antimicrobial peptides which when added as equimolar mixture exhibit a pronounced synergism in both their antibacterial and pore-forming activities. Here we show for the first time that the peptides assemble into defined supramolecular structures along the membrane interface. The resulting mesophases are quantitatively described by state-of-the art fluorescence self-quenching and correlation spectroscopies. Notably, the synergistic behavior of magainin 2 and PGLa correlates with the formation of hetero-domains and an order-of-magnitude increased membrane affinity of both peptides. Enhanced membrane association of the peptide mixture is only observed in the presence of phophatidylethanolamines but not of phosphatidylcholines, lipids that dominate bacterial and eukaryotic membranes, respectively. Thereby the increased membrane-affinity of the peptide mixtures not only explains their synergistic antimicrobial activity, but at the same time provides a new concept to increase the therapeutic window of combinatorial drugs.

Institut de Chimie UMR7177 CNRS University of Strasbourg 1 rue Blaise Pascal 67000 Strasbourg France

Institut de Chimie UMR7177 CNRS University of Strasbourg 1 rue Blaise Pascal 67000 Strasbourg France Institut Universitaire de France Paris France

J Heyrovský Institute of Physical Chemistry v v i Czech Academy of Sciences Dolejškova 2155 3 182 23 Prague Czech Republic

J Heyrovský Institute of Physical Chemistry v v i Czech Academy of Sciences Dolejškova 2155 3 182 23 Prague Czech Republic Institut für Angewandte Physik and Center for Functional Nanostructures Karlsruhe Institute of Technology Wolfgang Gaede Straße 1 76131 Karlsruhe Germany

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