Aromatic group-induced self-assembly of short antimicrobial peptides: unveiling exceptionally potent antimicrobial efficacy.

Self-assembled antimicrobial peptides (AMPs) have superior antimicrobial properties from their supramolecular nanostructures. A systematic study is needed to determine which AMPs can generate more significant self-assembled structures for antimicrobial activity. In this study, thirty-six self-assembled AMPs were systematically designed by combining six hexapeptide sequences with five aromatic groups, exploring the contributions of different sequences and groups to self-assembly and antimicrobial properties. Most peptides had broad-spectrum antimicrobial and self-assembly capabilities. Moderate self-assembly can endow these new AMPs with excellent antimicrobial properties. Candidate peptides Nap-f5f6 and Npx-f5f6 had outstanding antimicrobial activity, low toxicity, and high selectivity. This may be due to their self-assembly into nanofibers and nanospheres via π-π stacking provided by C- and N-terminal aromatic groups. Their membrane-disrupting bactericidal mechanism gives a rapid effect and prevents antibiotic resistance. Also, in infected mouse skin wounds, Nap-f5f6 and Npx-f5f6 had low toxicity, reduced bacterial load, and accelerated wound healing.