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The multiple sclerosis drug fingolimod induces pore-like membrane defects, contributing to its antimicrobial activity

Year: 2026

Type: article

Abstract: Although receptor-mediated mechanisms account for the therapeutic action of numerous FDA-approved drugs, emerging evidence suggests that many of these therapeutics have off-target antimicrobial activities. One example is fingolimod, an immunomodulator used to treat multiple sclerosis, that has been reported to have antimicrobial effects associated with membrane permeabilization. Yet the molecular mechanism by which fingolimod alters bacterial membranes remains unknown. As a cationic amphiphilic drug (CAD), fingolimod is comprised of both hydrophobic and positively charged regions that can enable membrane interactions. We show that fingolimod compromises membrane integrity in E. coli and P. aeruginosa , contributing to its antimicrobial activity. To determine how fingolimod disrupts membrane integrity, we used planar lipid bilayer electrophysiology with phospholipid compositions mimicking E. coli membranes. Using gramicidin A channels as molecular biosensors, we show that fingolimod alters both mechanical properties and surface charge of lipid bilayers at concentrations that have antimicrobial effects. At higher concentrations, fingolimod induces pore-like defects, as revealed by conductance measurements. The Bilayer Overtone Analysis suggests an autocatalytic mechanism for the exchange of fingolimod between opposing lipid leaflets. Molecular dynamics simulations correlate fingolimod's preference for pore-favoring curvature with its strong interactions with lipids and trans-leaflet translocation. These findings point to a molecular mechanism for fingolimod's off-target activity and provide a basis for understanding how some CAD structures can contribute to membrane-specific effects that compromise bacterial physiology.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2026.113164