Lipid-specific binding of the calcium-dependent antibiotic daptomycin leads to changes in lipid polymorphism of model membranes

Abstract

Daptomycin is a cyclic anionic lipopeptide with an antibiotic activity that is completely dependent on the presence of calcium (as Ca 2+). In a previous study [Jung et al., 2004. Chem. Biol. 11, 949–957], it was concluded that daptomycin underwent two Ca 2+-dependent structural transitions, whereby the first transition was solely dependent on Ca 2+, while the second transition was dependent on both Ca 2+ and the presence of negatively charged lipids that allowed daptomycin to insert into and perturb bilayer membranes with acidic character. Differences in the interaction of daptomycin with acidic and neutral membranes were further investigated by spectroscopic means. The lack of quenching of intrinsic fluorescence by the water-soluble quencher, KI, confirmed the insertion of the daptomycin Trp residue into the membrane bilayer, while the kynurenine residue was inaccessible even in an aqueous environment. Differential scanning calorimetry (DSC) indicated that the binding of daptomycin to neutral bilayers occurred through a combination of electrostatic and hydrophobic interactions, while the binding of daptomycin to bilayers containing acidic lipids primarily involved electrostatic interactions. The binding of daptomycin to acidic membranes led to the induction of non-lamellar lipid phases and membrane fusion.