Mechanistic Insights into the Membrane Permeabilization Activity of Antimicrobial Prenylated Isoflavonoids: A Comparative Study of Glabridin, Wighteone, and Lupiwighteone

Prenylated isoflavonoids have shown remarkable antimicrobial activity. Previous studies showed that the antimicrobial compounds glabridin and wighteone induced membrane permeabilization in microbial cells. Other compounds, such as lupiwighteone, showed no antimicrobial activity. In this study, the permeabilization efficacy and interaction with lipid bilayers of glabridin, wighteone, and lupiwighteone were assessed in vitro and in silico using model membranes. Permeabilization of liposomes by glabridin and wighteone confirmed the lipid bilayer as the primary target. Notably, lupiwighteone did not induce the permeabilization of liposomes. Molecular dynamics (MD) simulations were used to study the interaction of these compounds with phospholipid membranes. The calculated potential of mean force profiles for the three molecules correlated with liposome permeabilization, indicating a favorable intercalation inside the lipid bilayer for wighteone, followed by glabridin, and an unfavorable intercalation for lupiwighteone. Additionally, MD simulations indicated that the location of glabridin and wighteone in the membrane was just below the head groups. Furthermore, this study underscored the importance of partitioning between polar and hydrophobic areas for prenylated isoflavonoids, which conceivably determines the membrane insertion and, subsequently, the antimicrobial activity. Overall, this study showed that interactions with and permeabilization of the lipid bilayer are key factors for the antimicrobial activity of these compounds.