Interactions between fluoroquinolones and lipids : biophysical studies

Abstract

Probing fluoroquinolones/lipid interactions at the molecular level represents an important challenge in both membrane biophysics and pharmaceutical research. As the pharmacological target of these antibiotics is intracellular, they must pass across the bacterial membranes. Likewise, fluoroquinolones enter eukaryotic cells, which imply their ability of interacting with lipids membranes. In this context, the aim of my Thesis has been to characterize the effect of two closely related fluoroquinolones, ciprofloxacin and moxifloxacin, on physicochemical properties of the major phospholipids DPPG and DOPC/DPPC that are mimicking the prokaryotic and eukaryotic lipid membranes, respectively, by means of biophysical methods. First, I have studied the effect of these drugs on domains lipids erosion, lipids packing and their ability of modifying the conformation and orientation of the acyl chain(s) of phospholipids. Second, I have determined the binding affinities of ciprofloxacin to different model lipid membranes (DPPG, DPPC) and its effects on head group mobility and on thermotropic profile of these two phospholipids. The data reported in this Thesis point to different effects of ciprofloxacin and moxifloxacin on the phospholipids tested. Indeed, moxifloxacin induces more changes in the acyl chain conformation of phospholipids and has more lipid packing effects than ciprofloxacin. The latter interacts primarily with the head groups of lipids, and thereby modifies the orientation of the acyl chain. Thus, the first step in the interaction of ciprofloxacin with lipid membranes relates to its binding to these headgroups, which is stronger with negatively charged (DPPG) than with zwitterionic phospholipids (DPPC). Conversely, our results suggest that moxifloxacin is located in a more hydrophobic environment of the membranes, probably by creating a pocket in the interior of the lipid bilayer. These contrasting behaviors may be related to the fact that ciprofloxacin is, globally speaking, a more hydrophilic drug than moxifloxacin. Our work may help in shedding more light on the role played by lipids in the transport of fluoroquinolones in both prokaryotic and eukaryotic cells.(FARM 3) -- UCL, 201