Lipid Composition-Dependent Membrane Fragmentation
and Pore-Forming Mechanisms of Membrane Disruption by Pexiganan (MSI-78)
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Abstract
The
potency and selectivity of many antimicrobial peptides (AMPs)
are correlated with their ability to interact with and disrupt the
bacterial cell membrane. <i>In vitro</i> experiments using
model membranes have been used to determine the mechanism of membrane
disruption of AMPs. Because the mechanism of action of an AMP depends
on the ability of the model membrane to accurately mimic the cell
membrane, it is important to understand the effect of membrane composition.
Anionic lipids that are present in the outer membrane of prokaryotes
but are less common in eukaryotic membranes are usually thought to
be key for the bacterial selectivity of AMPs. We show by fluorescence
measurements of peptide-induced membrane permeabilization that the
presence of anionic lipids at high concentrations can actually inhibit
membrane disruption by the AMP MSI-78 (pexiganan), a representative
of a large class of highly cationic AMPs. Paramagnetic quenching studies
suggest MSI-78 is in a surface-associated inactive mode in anionic
sodium dodecyl sulfate micelles but is in a deeply buried and presumably
more active mode in zwitterionic dodecylphosphocholine micelles. Furthermore,
a switch in mechanism occurs with lipid composition. Membrane fragmentation
with MSI-78 can be observed in mixed vesicles containing both anionic
and zwitterionic lipids but not in vesicles composed of a single lipid
of either type. These findings suggest membrane affinity and membrane
permeabilization are not always correlated, and additional effects
that may be more reflective of the actual cellular environment can
be seen as the complexity of the model membranes is increased