A pronounced membrane selectivity is demonstrated for short, hydrophilic, and highly charged
antimicrobial peptides, end-tagged with
aromatic amino acid stretches. The mechanisms underlying this were investigated by a method combination of fluorescence and CD spectroscopy, ellipsometry, and Langmuir balance measurements, as well as with functional assays on cell toxicity and antimicrobial effects. End-tagging with oligotryptophan promotes
peptide-induced lysis of
phospholipid liposomes, as well as membrane
rupture and killing of bacteria and fungi. This antimicrobial potency is accompanied by limited toxicity for human epithelial cells and low
hemolysis. The functional selectivity displayed correlates to a pronounced selectivity of such
peptides for anionic
lipid membranes, combined with a markedly reduced membrane activity in the presence of
cholesterol. As exemplified for GRR10W4N (GRRPRPRPRPWWWW-NH(2)), potent
liposome rupture occurs for anionic
lipid systems (
dioleoylphosphatidylethanolamine (DOPE)/dioleoylphosphatidylglycerol (
DOPG) and Escherichia coli
lipid extract) while that of zwitterionic
dioleoylphosphatidylcholine (
DOPC)/
cholesterol is largely absent under the conditions investigated. This pronounced membrane selectivity is due to both a lower
peptide binding to the zwitterionic membranes (z≈-8-10mV) than to the anionic ones (z≈-35-40mV), and a lower degree of membrane incorporation in the zwitterionic membranes, particularly in the presence of
cholesterol. Replacing
cholesterol with
ergosterol, thus mimicking fungal membranes, results in an increased sensitivity for
peptide-induced lysis, in analogy to the antifungal properties of such
peptides. Finally, the generality of the high membrane selectivity for other
peptides of this type is demonstrated.