Aromatic Fluorination Enhances the Hydrophobicity and Antimicrobial Activity of Magainin 2.

Abstract

Inspired by the structure of the natural antimicrobial peptide magainin 2 (MG), we developed a series of fluorinated magainin 2 analogues (FMGs) incorporating pentafluorophenylalanine residue and systematically studied their physicochemical properties and antimicrobial activities. Analytical reverse-phase high-performance liquid chromatography and circular dichroism spectroscopy demonstrated that incorporation of pentafluorophenylalanines effectively modulates the hydrophobicity and secondary structure of peptides. Membrane-disruption assays using model lipid bilayers, together with evaluations of antibacterial activity assays against Escherichia coli (E. coli) and hemolytic toxicity assays toward red blood cells, revealed that FMGs exhibit enhanced antimicrobial activity, with minimum inhibitory concentration values reduced by up to an order of magnitude relative to MG, without a substantial increase in toxicity. Notably, FMGs also retained superior antibacterial activity against a drug-resistant E. coli strain harboring the RP4 multidrug-resistance plasmid. Molecular dynamics simulations suggested that the preferential membrane-disruptive activity arises from selective binding to negatively charged bacterial membranes. These findings provide detailed structure-activity relationships for fluorinated antimicrobial peptides and highlight the introduction of fluorinated aromatic units as a powerful strategy to enhance hydrophobicity and antimicrobial activity.