Selectivity of cateslytin for fungi: the role of acidic lipid-ergosterol membrane fluidity in antimicrobial action.
The specificity of the stress-produced antimicrobial peptide cateslytin to fungi membranes has been investigated using complex membrane models made of zwitterionic and negatively charged lipids, cholesterol, or ergosterol. Noninvasive solid-state NMR of deuterated neutral and negatively charged lipids, together with IR spectroscopy, afforded following both changes in membrane fluidity and in peptide secondary structure. Cateslytin, by adopting an aggregated antiparallel beta-sheeted structure at membrane interfaces, induces a fluid/rigid membrane separation on ergosterol-containing models only. This effect is accounted for by a 2-fold electronic interaction: attractive dipole-dipole between basic arginine residues and negatively charged lipid head groups, and attractive cation-pi between arginine and the conjugated pi electrons of the ergosterol fused-ring system. This complex leads to fluid/thinner membranes that laterally separate out from rigid/thicker membranes that are not bound by cateslytin. The boundary defects occurring between domains span several angstroms, as probed by NMR of perdeuterated lipids, and are proposed to trigger peptide permeation through membranes. The intrinsic greater membrane fluidity of ergosterol/acidic lipid components in fungi is shown to be one of the key factors for specific cateslytin biological action.
Jean-François
Frantz
F
UMR 5248 CBMN, CNRS-Université-Bordeaux-ENITAB, IECB, 2 rue Robert Escarpit, 33607 Pessac, France. jean-francois@magnet.fsu.edu
Desbat
Bernard
B
Dufourc
Erick J
EJ
D000935:Antifungal Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D002176:Candida albicans / Q000187:drug effects*; D053379:Chromogranin A / Q000494:pharmacology*; D004875:Ergosterol / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry; D008560:Membrane Fluidity / Q000187:drug effects*; D008563:Membrane Lipids / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000494:pharmacology*
D000935:Antifungal Agents; D023181:Antimicrobial Cationic Peptides; D053379:Chromogranin A; D008051:Lipid Bilayers; D008563:Membrane Lipids; D010446:Peptide Fragments; C527456:chromogranin A (344-358); D004875:Ergosterol