Gemini Peptide Amphiphiles with Broad-Spectrum Antimicrobial Activity and Potent Antibiofilm Capacity.

To address the challenge from microbial resistance and biofilm, this work develops three gemini peptide amphiphiles with basic tetrapeptide spacers 12-(Arg)4-12, 12-(Lys)4-12, and 12-(His)4-12 and finds that they exhibit varied antimicrobial/antibiofilm activities. 12-(Arg)4-12 shows the best performance, possessing the broad-spectrum antimicrobial activity and excellent antibiofilm capacity. The antimicrobial and antibiofilm activities strongly depend on the membrane permeation and self-assembling structure of these peptide amphiphiles. Gemini peptide amphiphile with highly polar arginine as the spacer, 12-(Arg)4-12, self-assembles into short rods that are prone to dissociate into monomers for permeating and lysing membrane , leading to its broad-spectrum antimicrobial activity and high efficiency in eradicating biofilm. Long rods formed by relatively weaker polar 12-(Lys)4-12 are less prone to disassemble into monomers for further membrane permeation, which makes it selectively kill more negatively charged bacteria and endow it medium antibiofilm activity. Low polar 12-(His)4-12 aggregates into long fibers, which are very difficult to dissociate and they mainly electrostatically bind on the negative microbial surface, resulting in its weakest antimicrobial and antibiofilm activity. This study reveals the effect of the antimicrobial peptide structure and aggregation on the antimicrobial activities and would be helpful for developing high-efficient antimicrobial peptides with antibiofilm activity.