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Interaction of fusidic acid with lipid membranes: Implications to the mechanism of antibiotic activity

Falck, Emma; Hautala, Jari T.; Karttunen, Mikko; Kinnunen, Paavo K. J.; Patra, Michael LU ; Saaren-Seppala, Heikki; Vattulainen, Ilpo; Wiedmer, Susanne K. and Holopainen, Juha M. (2006) In Biophysical Journal 91(5). p.1787-1799
Abstract
We have studied the effects of cholesterol and steroid-based antibiotic fusidic acid (FA) on the behavior of lipid bilayers using a variety of experimental techniques together with atomic-scale molecular dynamics simulations. Capillary electrophoretic measurements showed that FA was incorporated into fluid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine membranes. Differential scanning calorimetry in turn showed that FA only slightly altered the thermodynamic properties of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers, whereas cholesterol abolished all endotherms when the mole fraction of cholesterol (X-chol) was > 0.20. Fluorescence spectroscopy was then used to further characterize the influence of these two steroids on... (More)
We have studied the effects of cholesterol and steroid-based antibiotic fusidic acid (FA) on the behavior of lipid bilayers using a variety of experimental techniques together with atomic-scale molecular dynamics simulations. Capillary electrophoretic measurements showed that FA was incorporated into fluid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine membranes. Differential scanning calorimetry in turn showed that FA only slightly altered the thermodynamic properties of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers, whereas cholesterol abolished all endotherms when the mole fraction of cholesterol (X-chol) was > 0.20. Fluorescence spectroscopy was then used to further characterize the influence of these two steroids on DPPC large unilamellar vesicles. In the case of FA, our result strongly suggested that FA was organized into lateral microdomains with increased water penetration into the membrane. For cholesterol/DPPC mixtures, fluorescence spectroscopy results were compatible with the formation of the liquid-ordered phase. A comparison of FA and cholesterol-induced effects on DPPC bilayers through atomistic molecular dynamics simulations showed that both FA and cholesterol tend to order neighboring lipid chains. However, the ordering effect of FA was slightly weaker than that of cholesterol, and especially for deprotonated FA the difference was significant. Summarizing, our results show that FA is readily incorporated into the lipid bilayer where it is likely to be enriched into lateral microdomains. These domains could facilitate the association of elongation actor-G into lipid rafts in living bacteria, enhancing markedly the antibiotic efficacy of FA. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biophysical Journal
volume
91
issue
5
pages
1787 - 1799
publisher
Cell Press
external identifiers
  • pmid:16782792
  • wos:000239790400024
  • scopus:33748459256
ISSN
1542-0086
DOI
10.1529/biophysj.106.084525
language
English
LU publication?
yes
id
a3ff5af8-c935-41f9-9310-3046b7c6a3ea (old id 397569)
date added to LUP
2007-10-02 19:25:27
date last changed
2019-09-11 01:27:23
@article{a3ff5af8-c935-41f9-9310-3046b7c6a3ea,
  abstract     = {We have studied the effects of cholesterol and steroid-based antibiotic fusidic acid (FA) on the behavior of lipid bilayers using a variety of experimental techniques together with atomic-scale molecular dynamics simulations. Capillary electrophoretic measurements showed that FA was incorporated into fluid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine membranes. Differential scanning calorimetry in turn showed that FA only slightly altered the thermodynamic properties of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers, whereas cholesterol abolished all endotherms when the mole fraction of cholesterol (X-chol) was > 0.20. Fluorescence spectroscopy was then used to further characterize the influence of these two steroids on DPPC large unilamellar vesicles. In the case of FA, our result strongly suggested that FA was organized into lateral microdomains with increased water penetration into the membrane. For cholesterol/DPPC mixtures, fluorescence spectroscopy results were compatible with the formation of the liquid-ordered phase. A comparison of FA and cholesterol-induced effects on DPPC bilayers through atomistic molecular dynamics simulations showed that both FA and cholesterol tend to order neighboring lipid chains. However, the ordering effect of FA was slightly weaker than that of cholesterol, and especially for deprotonated FA the difference was significant. Summarizing, our results show that FA is readily incorporated into the lipid bilayer where it is likely to be enriched into lateral microdomains. These domains could facilitate the association of elongation actor-G into lipid rafts in living bacteria, enhancing markedly the antibiotic efficacy of FA.},
  author       = {Falck, Emma and Hautala, Jari T. and Karttunen, Mikko and Kinnunen, Paavo K. J. and Patra, Michael and Saaren-Seppala, Heikki and Vattulainen, Ilpo and Wiedmer, Susanne K. and Holopainen, Juha M.},
  issn         = {1542-0086},
  language     = {eng},
  number       = {5},
  pages        = {1787--1799},
  publisher    = {Cell Press},
  series       = {Biophysical Journal},
  title        = {Interaction of fusidic acid with lipid membranes: Implications to the mechanism of antibiotic activity},
  url          = {http://dx.doi.org/10.1529/biophysj.106.084525},
  volume       = {91},
  year         = {2006},
}