Molecular Basis for Membrane Selectivity of an Antimicrobial Peptide, Magainin 2

Abstract

Magainin peptides, isolated from Xenopus skin, kill bacteria by permeabilizing their cell membranes whereas they do not lyse erythrocytes. To elucidate the rationale for this membrane selectivity, we compared the effects of the membrane lipid composition and the transmembrane potential on the membrane-lytic power of magainin 2 with that of hemolytic melittin. The activity of magainin to zwitterionic phospholipids constituting the erythrocyte surface was extremely weak compared with that of melittin, and acidic phospholipids are necessary for effective action. The presence of sterols reduced the susceptibility of the membrane to magainin. The generation of an inside-negative transmembrane potential enhanced magainin-induced hemolysis. We can conclude that the absence of any acidic phospholipids on the outer monolayer and the abundant presence of cholesterol, combined with the lack of the transmembrane potential, contribute to the protection of erythrocytes from magainin's attack.

Translocation of Analogues of the Antimicrobial Peptides Magainin and Buforin across Human Cell Membranes

“…Their affinities for mammalian cells, on the surface of which anionic phospholipids are not exposed, have been considered to be low, although weak hydrophobic interaction drives peptide binding (34). The amounts of MG2d taken up by both cells were larger than those of BF2d and Tat-(47-57) (Fig.…”

Structure-Activity Relationships of Diastereomeric Lysine Ring Size Analogs of the Antimicrobial Peptide Gramicidin S

“…In turn, this implies that differences between the bulk physicochemical properties of bacterial and animal cell membranes, and more specifically between the properties of their polar/ apolar interfacial regions (the presumed location of these peptides in lipid membranes), are the primary basis for their capacity to discriminate between the two types of membranes. This possibility is one of the hypotheses guiding current attempts at the rational design of therapeutically useful antimicrobial peptides (44,45), and our studies of GS and its analogs are consistent with this premise (16,23). 2 A comparison of the lipid compositions of bacterial and erythrocyte membranes indicates that the main compositional differences between these naturally occurring membranes are that the outer surfaces of erythrocyte membranes are composed of predominantly zwitterionic phospholipids and substantial amounts of cholesterol, whereas the outer surfaces of bacterial membranes are devoid of cholesterol and contain significant amounts (ϳ20 -40 mol%) of negatively charged phospholipids (43,46).…”

Broad spectrum antibiotic activity of skin‐PYY

“…According to this hypothesis, upon association of the peptide at the membrane surface via electrostatic interactions, the amphipathic helix penetrates in the membrane and perturbs its structure, which results in rapid osmolysis. Moreover, since peptide-membrane interactions are governed by their respective physico-chemical properties (amphipathy, peptide length, charge distribution, lipid composition) it was postulated that lack of toxicity towards mammalian cells is due to the weak-or lack of interactions between these peptides and mammalian membranes [25,26]. Therefore, one expects that mild perturbation of the membrane structure may simply lead in some cases to non-fatal cross-membrane leakage of ions and other small molecules from high-to low concentration.…”