Peptide induced demixing in PG/PE lipid mixtures: A mechanism for the specificity of antimicrobial peptides towards bacterial membranes?

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Abstract

Antimicrobial peptides attract a lot of interest as potential candidates to overcome bacterial resistance. So far, nearly all the proposed scenarios for their mechanism of action are associated with perforating and breaking down bacterial membranes after a binding process. In this study we obtained additional information on peptide induced demixing of bacterial membranes as a possible mechanism of specificity of antimicrobial peptides. We used DSC and FT-IR to study the influence of a linear and cyclic arginine- and tryptophan-rich antimicrobial peptide having the same sequence (RRWWRF) on the thermotropic phase transitions of lipid membranes. The cyclization of the peptide was found to enhance its antimicrobial activity and selectivity ( Dathe, M. Nikolenko, H. Klose, J. Bienert, M. Biochemistry 43 (2004) 9140–9150). A particular preference of the binding of the peptides to DPPG headgroups compared to other headgroups of negatively charged phospholipids, namely DMPA, DPPS and cardiolipin was observed. The main transition temperature of DPPG bilayers was considerably decreased by the bound peptides. The peptides caused a substantial down-shift of the transition of DPPG/DMPC. In contrast, they induced a demixing in DPPG/DPPE bilayers and led to the appearance of two peaks in the DSC curves indicating a DPPG-peptide-enriched domain and a DPPE-enriched domain. These results could be confirmed by FT-IR-spectroscopic measurements. We therefore propose that the observed peptide-induced lipid demixing in PG/PE-membranes could be a further specific effect of the antimicrobial peptides operating only on bacterial membranes, which contain appreciable amounts of PE and PG, and which could in principle also occur in liquid–crystalline membranes.

Abbreviations

DSC
Differential scanning calorimetry
FT-IR
Fourier transform infrared
DMPC
1,2-dimyristoyl-sn-glycero-3-phosphocholine
DPPE
1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine
DPPG
1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol)
DMPA
1,2-dimyristoyl-sn-glycero-3-phosphatidic acid
DPPS
1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine
TMCL
1,1′,2,2′-tetramyristoyl cardiolipin
PC
Phosphatidylcholine
PE
Phosphatidylethanolamine
PG
Phosphatidylglycerol
PA
Phosphatidic acid
PS
Phosphatidylserine
CL
Cardiolipin
CAMP
Cationic antimicrobial peptide
Tm
Lipid phase transition temperature

Keywords

Antimicrobial peptide
Model lipid membrane
Lipid demixing
Lipid–peptide interaction
DSC
FT-IR

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