Multiple Sclerosis Drug Fingolimod Exhibits Antibacterial Activity through Bacterial Membrane Permeabilization

Area of Science:

• Membrane biophysics
• Drug discovery
• Antimicrobial mechanisms

Background:

• Many FDA-approved drugs exhibit off-target antimicrobial activity by affecting cell membranes.
• Fingolimod, an immunomodulator, has known antimicrobial effects, but its mechanism of action on bacterial membranes is unclear.
• Understanding drug-membrane interactions is crucial for drug repurposing and identifying unintended side effects.

Purpose of the Study:

• To elucidate the molecular mechanism by which fingolimod disrupts bacterial membrane integrity.
• To investigate fingolimod's interaction with bacterial membranes and its contribution to antimicrobial activity.

Main Methods:

• Planar lipid bilayer electrophysiology using E. coli-mimicking lipid compositions.
• Gramicidin A channels as molecular biosensors to probe membrane properties.
• Bilayer Overtone Analysis and molecular dynamics simulations.

Main Results:

• Fingolimod compromises membrane integrity in E. coli and P. aeruginosa.
• It alters lipid bilayer mechanical properties and surface charge at antimicrobial concentrations.
• At higher concentrations, fingolimod directly permeabilizes lipid bilayers, showing a preference for pore-favoring curvature.

Conclusions:

• Fingolimod's off-target antimicrobial activity is mediated by direct disruption of bacterial membrane integrity.
• The study establishes a molecular mechanism for fingolimod's membrane-related effects.
• Findings provide insights into designing cationic amphiphilic drugs (CADs) with specific membrane interactions for therapeutic or antimicrobial purposes.