Revolutionizing Antimicrobial Biomaterials: Integrating an Enzyme Degradation-Resistant Sequence into Self-Assembled Nanosystems to Overcome Stability Limitations of Peptide-Based Drugs

Abstract

Incorporating enzyme-resistant peptide sequences into self-assembled nanosystems is a promising strategy to enhance the stability and versatility of peptide-based antibacterial drugs, aiming to replace ineffective antibiotics. By combining newly designed enzymatic-resistant sequences with synthetically derived compounds bearing single, double, triple, or quadruple aromatic rings. A series of nanoscale antimicrobial self-assembled short peptides for the purpose of combating bacterial infections are generated. Nap* (Nap–^DNal–Nal–Dab–Dab–NH₂, where Nap represents the 1-naphthylacetyl group) possesses the greatest clinical potential (GM_SI = 23.96) among the peptides in this series. At high concentrations in an aqueous environment, Nap* spontaneously generates nanofibers to capture bacteria and prevent their evasion, exhibiting broad-spectrum antimicrobial effects and exceptional biocompatibility. In the presence of physiological salt ions and serum, the antimicrobial agent exhibits strong effectiveness and retains impressive resistance even when exposed to high levels of proteases (trypsin, chymotrypsin, pepsin). Nap* exhibits negligible in vivo toxicity and effectively alleviates systemic bacterial infections in mice. Mechanistically, Nap* initially captures bacteria and induces bacterial cell death primarily through membrane dissolution, achieved by multiple synergistic mechanisms. In summary, these advances have the potential to greatly expedite the clinical evolution of nanomaterials based on short peptides combined with naphthyl groups and foster the development of peptides integrated with self-assembled systems in this domain.

Graphical Abstract