Bensikaddour Hayet, Fa Nathalie, Burton Ingrid, Deleu Magali, Lins Laurence, Schanck André, Brasseur Robert, Dufrêne Yves F, Goormaghtigh Erik, Mingeot-Leclercq Marie-Paule
Université Catholique de Louvain, Faculty of Medicine, Unité de Pharmacologie Cellulaire et Moléculaire, Brussels, Belgium.
Biophys J. 2008 Apr 15;94(8):3035-46. doi: 10.1529/biophysj.107.114843. Epub 2008 Jan 4.
Probing drug/lipid interactions at the molecular level represents an important challenge in pharmaceutical research and membrane biophysics. Previous studies showed differences in accumulation and intracellular activity between two fluoroquinolones, ciprofloxacin and moxifloxacin, that may actually result from their differential susceptibility to efflux by the ciprofloxacin transporter. In view of the critical role of lipids for the drug cellular uptake and differences observed for the two closely related fluoroquinolones, we investigated the interactions of these two antibiotics with lipids, using an array of complementary techniques. Moxifloxacin induced, to a greater extent than ciprofloxacin, an erosion of the DPPC domains in the DOPC fluid phase (atomic force microscopy) and a shift of the surface pressure-area isotherms of DOPC/DPPC/fluoroquinolone monolayer toward lower area per molecule (Langmuir studies). These effects are related to a lower propensity of moxifloxacin to be released from lipid to aqueous phase (determined by phase transfer studies and conformational analysis) and a marked decrease of all-trans conformation of acyl-lipid chains of DPPC (determined by ATR-FTIR) without increase of lipid disorder and change in the tilt between the normal and the germanium surface (also determined by ATR-FTIR). All together, differences of ciprofloxacin as compared to moxifloxacin in their interactions with lipids could explain differences in their cellular accumulation and susceptibility to efflux transporters.
在分子水平上探究药物与脂质的相互作用是药物研究和膜生物物理学中的一项重要挑战。先前的研究表明，两种氟喹诺酮类药物环丙沙星和莫西沙星在积累和细胞内活性方面存在差异，这实际上可能是由于它们对环丙沙星转运蛋白外排的敏感性不同所致。鉴于脂质对药物细胞摄取的关键作用以及两种密切相关的氟喹诺酮类药物之间观察到的差异，我们使用一系列互补技术研究了这两种抗生素与脂质的相互作用。与环丙沙星相比，莫西沙星在更大程度上导致了DOPC流体相中DPPC结构域的侵蚀（原子力显微镜），以及DOPC/DPPC/氟喹诺酮单层表面压力-面积等温线向每分子更低面积的移动（Langmuir研究）。这些效应与莫西沙星从脂质释放到水相的倾向较低（由相转移研究和构象分析确定）以及DPPC酰基脂质链的全反式构象显著降低（由ATR-FTIR确定）有关，而脂质无序性没有增加，法线与锗表面之间的倾斜度也没有变化（也由ATR-FTIR确定）。总之，环丙沙星与莫西沙星在与脂质相互作用方面的差异可以解释它们在细胞积累和对外排转运蛋白敏感性方面的差异。
