Interaction of Fusidic Acid with Lipid Membranes: Implications to the Mechanism of Antibiotic Activity Export

@article{citeulike:2269543, 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 (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. 10.1529/biophysj.106.084525}, author = {Falck, Emma and Hautala, Jari T. and Karttunen, Mikko and Kinnunen, Paavo K. and Patra, Michael and Saaren-Seppala, Heikki and Vattulainen, Ilpo and Wiedmer, Susanne K. and Holopainen, Juha M.}, citeulike-article-id = {2269543}, citeulike-linkout-0 = {http://dx.doi.org/10.1529/biophysj.106.084525}, citeulike-linkout-1 = {http://www.biophysj.org/cgi/content/abstract/91/5/1787}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16782792}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16782792}, day = {1}, doi = {10.1529/biophysj.106.084525}, journal = {Biophys. J.}, keywords = {antibiotics, fusidine}, month = {September}, number = {5}, pages = {1787--1799}, posted-at = {2008-01-21 18:00:01}, priority = {2}, 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} }

TY - JOUR ID - citeulike:2269543 L3 - citeulike-article-id:2269543 N2 - 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. 10.1529/biophysj.106.084525 IS - 5 JF - Biophys. J. EP - 1799 TI - Interaction of Fusidic Acid with Lipid Membranes: Implications to the Mechanism of Antibiotic Activity VL - 91 SP - 1787 KW - antibiotics KW - fusidine AU - Falck, Emma AU - Hautala, Jari AU - Karttunen, Mikko AU - Kinnunen, Paavo AU - Patra, Michael AU - Saaren-Seppala, Heikki AU - Vattulainen, Ilpo AU - Wiedmer, Susanne AU - Holopainen, Juha PY - 2006/09/01/ UR - http://dx.doi.org/10.1529/biophysj.106.084525 ER -