Most FDA-approved drugs act through receptor binding; however, recent studies have shown that many also alter lipid membrane properties, often as an underappreciated effect. One such cationic amphiphilic drug (CAD) is fingolimod, an immunomodulator for treating multiple sclerosis (MS) has been shown to inhibit bacterial growth and induce cell membrane permeabilization. However, the precise effects of CADs on bacterial membrane structure, integrity, and membrane-resident protein activity remain unclear and are the focus of our investigation. Based on their amphiphilic nature, we hypothesize that CADs can influence the hydrophobic membrane core and negatively charged phospholipid head groups, potentially modifying membrane integrity and ion channel behavior. We study how the fingolimod, a sphingosine-1-phosphate receptor modulator, alters the mechanical properties of planar membranes, mimicking E. coli outer membrane lipid composition, using gramicidin A (grA) channel as a molecular biosensor. GrA channel amplitude and lifetime, respond to membrane CAD-induced modifications such as surface charge and hydrophobic core properties. We found that fingolimod modifies lipid bilayer properties in a dose-dependent manner and, at higher concentrations (>4 μM), induces membrane permeabilization, as supported by the data from unmodified membrane assays, thereby potentially affecting membrane proteins in organelles. These results suggest a broader perspective on the CAD’s action, highlighting membrane modulation as a mechanistically relevant component that links biophysical membrane properties to functional effects. Understanding the bacterial membrane-specific effects of CADs will ultimately provide critical insights for their therapeutic potential as antimicrobial agents and possible side effects.
Syam et al. (Sun,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: