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* Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois; Laboratory of Analytical Chemistry, Department of Chemistry, University of Helsinki, Helsinki, Finland; Department of Applied Mathematics, The University of Western Ontario, London, Ontario, Canada; Biophysics and Statistical Mechanics Group, Laboratory for Computational Engineering, Helsinki University of Technology, Helsinki, Finland; ¶ Helsinki Biophysics and Biomembrane Group, Institute of Biomedicine, Biomedicum, University of Helsinki, Helsinki, Finland; || Physical Chemistry 1, Lund University, Lund, Sweden; ** Department of Ophthalmology, University of Helsinki, Helsinki, Finland; Department of Ophthalmology, Itä-Savo Hospital District, Helsinki, Finland; Laboratory of Physics and Helsinki Institute of Physics, Helsinki University of Technology, Helsinki, Finland; Institute of Physics, Tampere University of Technology, Tampere, Finland, and ¶¶ MEMPHYS-Center for Biomembrane Physics, Physics Department, University of Southern Denmark, Odense, Denmark
Correspondence: Address reprint requests to Juha Holopainen, Dept. of Ophthalmology, University of Helsinki, PO Box 220, FI-00029 HUS, Helsinki, Finland. Tel.: 358-9-471-77197; Fax: 358-9-471-73162, E-mail: holopainen.juha{at}gmail.com.
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 (Xchol) 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 factor-G into lipid rafts in living bacteria, enhancing markedly the antibiotic efficacy of FA.
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