Mechanism of Action and Membrane Interactions of Antibacterial Quaternized Triazolium Peptoids

Using antimicrobial peptides as a template, triazolium-based
peptoids
were designed with strong and selective antibacterial activities.
To probe their mechanism, eight distinct peptoids were investigated
using biophysical methods with lipid bilayers modeling bacterial or
eukaryotic membranes. Calcein leakage experiments closely parallel
antibacterial assays testing activities against Gram-negative or Gram-positive
bacteria and toxicity for human red blood cells. This excellent correlation
shows that the membrane-association underlies these peptoids’
biological activities. While circular dichroism spectroscopy confirms
their designed PPI (polyproline I) helical fold, fluorescence assays
quantitatively evaluate membrane association and indicate localization
at the membrane interface. In the presence of peptoids, a significant
reduction in lipid order parameters is observed by solid-state NMR
spectroscopy. Collectively, these findings support a membrane-mediated
mechanism of action for the triazolium-based peptoids similar to that
for linear cationic antimicrobial peptides. Furthermore, the physicochemical
and structural features of the peptoids explain their different degrees
of biological activities.