Improving the Antibacterial Activity of Tryptophan-Containing Peptide Nanostructures Through Self-Assembly

Antimicrobial peptides (AMPs) are frequently distributed in the tissues and organs of animals to exhibit broad-spectrum activities against various pathogens, and thus to constitute the first line of defense in the innate immune system of most living organisms. AMPs commonly exert antibiotic activities through nonreceptor-mediated membrane lysis of pathogenic organisms and the mechanism of this AMP-induced membrane lysis is generally attributed to their amphipathic nature. Although physicochemical attributes of AMPs, such as hydrophobicity and charge, have been demonstrated to govern their affinity toward biological membranes, the dimensional attributes evolving with self-assembly have yet to be elucidated for the design principle of synthetic AMPs. This work demonstrates that self-assembly effectively improves the antibacterial performance of Fmoc-capped, tryptophan (Trp)-containing peptides. Compared with nonassembled peptides in their monomeric state, indole chromophores of Trp, which exhibited a highly ordered spatial arrangement and were induced by self-assembly, resulted in stronger interactions between the resulting peptide nanostructures and model phospholipid membrane vesicles; these interactions led to greater activities against gram-positive and gram-negative bacteria. This work highlights that the spatial organization of peptide nanostructures evolve with self-assembly and strongly contribute to antibacterial activity, which enriches the design principles for novel synthetic short peptides with therapeutic use.