Conformation-activity relationship of a novel peptide antibiotic: structural characterization of dermaseptin DS 01 in media that mimic the membrane environment.

Dermaseptins, small polycationic peptides synthesized by amphibians, exert a lytic action on bacteria, protozoa, yeast, and filamentous fungi at micromolar concentrations, but unlike polylysines, show little hemolytic activity. Dermaseptins S are active only against bacteria and form aggregates at high peptide/lipid ratios, whereas dermaseptins B are active also against fungi and form aggregates at low peptide/lipid ratios. A new dermaseptin, named DS 01, from the skin secretion of Phyllomedusa oreades, showed not only strong antibacterial properties against Gram-positive and Gram-negative bacteria but also antiprotozoan activity in the microM range. An analysis of the sequences of all dermaseptins only shows a common tendency to adopt amphipathic helical conformations but does not hint at significant differences. In order to rationalize the biological differences among dermaseptins, it is necessary to analyze their conformational properties in greater detail. A structural characterization in media that mimic the membrane environment shows that the surface properties of DS 01, as compared to those of dermaseptins S1 and B2, are intermediate, in agreement with its peculiar pharmacological profile. The regular alternation of positive and negative patches on the surface suggests a plausible aggregation mechanism.