Abstract
Lipopeptides such as polymyxins, octapeptins or daptomycin often show an increased activity against bacteria as compared to their non-acylated analogue. Thus, we have studied N-acylated synthetic peptides derived from a fragment of human lactoferrin (LF-11) to elucidate the interaction of these peptides with Gram-negative and Gram-positive bacteria and membrane mimetic systems using various biophysical and biological methods.Calorimetric studies on liposomes composed of phosphatidylglycerol revealed that the parent peptide induced a phase separation into peptide-enriched and -poor domains, which however consist of a similar domain size as calculated by the cooperative units. In contrast, at the same lipid-to-peptide molar ratio (25:1) the N-acylated derivatives strongly broadened the phase transition range and lowered markedly the main transition temperature. This is indicative for rather small and inhomogeneous domains, which will result in large line defects increasing membrane permeability as observed in intact bacteria. Membrane destabilization of E. coli and S. aureus induced by the peptides was monitored by using the membrane-potential-sensitive dye DiIC1 and the extent of membrane damage caused by the peptides by the cationic dye SYTOX green, which cannot enter intact cells unless its membrane is disrupted by external compounds. In both assays the N-acylated peptides showed a dramatic increase of fluorescence indicating massive membrane damage. This is supported by electron micrographs, which clearly showed a loss of cytoplasmic content and membrane rupture in the presence of the N-acylated peptide. Nevertheless, the extent of cell membrane rupture does not necessarily strongly correlate with the MIC-value of the peptides emphasizing the different mode of interaction of (non)-acylated peptides, which in part may be related to different degree of interaction with cell membrane/wall components such as lipopolysaccharides and lipoteichoic acid.Acknowledgement to EC-projects “ANEPID” and “BIOCONTROL”
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