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Zwitterionic Phospholipids and Sterols Modulate Antimicrobial Peptide-Induced Membrane Destabilization

Faculté de chimie, Université Louis Pasteur/Centre National de la Recherche Scientifique UMR 7177, Institut le Bel, Strasbourg, France

Correspondence: Address reprint requests to A. James Mason, Dept. of Pharmacy, King's College London, 150 Stamford St., London SE1 9NH, UK. Tel.: 33-3-90-24-51-52; Fax: 33-3-90-24-51-63; E-mail: james.mason{at}kcl.ac.uk.

Cationic amphipathic -helical peptides preferentially disrupt anionic lipids in mixed model membranes, potentially causing a catastrophic release of the cell contents or attenuation of the membrane potential. The effective role of such peptides requires considerable discrimination between target and host cells, which is likely to occur at the level of the cell membrane. Here, we explore the roles of a variety of common membrane constituents in mediating the interaction between the antimicrobial peptide pleurocidin and model membranes. We employ intrinsic tryptophan fluorescence and circular dichroism to observe the effect of increasing concentrations of sterol in the membrane on peptide binding, using ²H solid-state NMR of chain deuterated lipids simultaneously to probe the effective chain disruption of the anionic phospholipid component of the membrane. We show that the degree of ordering of the lipid acyl chains in the membrane is dependent on the nature of the zwitterionic phospholipid headgroup in mixed anionic membranes. Furthermore, the presence of cholesterol and ergosterol increases acyl chain order in the liquid crystalline model membranes, but to differing degrees. Our results show how sterols can protect even negatively charged membranes from the disruptive effects of antimicrobial peptides, thereby providing a molecular view of the differences in sensitivity of various target membranes to linear cationic antibiotic peptides where bacteria (no sterols) are most susceptible, lower eukaryotes including fungi (containing ergosterol) exhibit an intermediate degree of sensitivity, and higher organisms (containing cholesterol) are largely resistant to antimicrobial peptides.

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