# Molecular Interactions of Fluoroquinolone Antibiotics with Lipid Membranes

## TL;DR

This study explores how the antibiotic levofloxacin interacts with lipid membranes, showing it prefers negatively charged membranes and forms molecular assemblies in solution.

## Contribution

The study reveals the molecular behavior of levofloxacin in solution and its preference for negatively charged lipid membranes using NMR and MD simulations.

## Key findings

- Levofloxacin self-associates in solution below its solubility limit, forming fast-exchange molecular assemblies.
- It shows a preference for associating with negatively charged lipid membranes over zwitterionic ones.
- MD simulations indicate levofloxacin condensation and partial insertion into lipid bilayers.

## Abstract

Levofloxacin is a broad-spectrum fluoroquinolone antibiotic
in
clinical use that targets DNA gyrase in the cytosol. It is used in
systemic applications via oral or intravenous route, and its pharmacokinetics
and access to its molecular targets are strongly influenced by interactions
with cellular membranes. We used NMR and MD simulations to investigate
the physical state of levofloxacin in solution and its interactions
with lipid membranes, assessing the role of membrane charge and antibiotic
concentration. Using zwitterionic DOPC and negatively charged DOPC/DOPG
lipid membranes, we observe concentration-dependent self-association
of levofloxacin in solution below its solubility limits and association
with lipid membranes with a preference for negatively charged bilayers.
Below the solubility limit, levofloxacin solutions that appear clear
contain self-associated molecular assemblies in fast exchange equilibrium
with a monomeric soluble population. In the presence of lipid membranes,
this equilibrium is shifted in favor of a membrane-associated population
with preference for negative lipids. MD simulations show levofloxacin
condensation in solution and fractional membrane insertion, which
suggest the presence of a molecular population embedded in the lipid
bilayer, coexisting with self-associated levofloxacin molecular “droplets”
in exchange with a solvated population.