Abstract
The excessive use of antibiotics in recent years has contributed to an increase in microbial resistance, thereby compromising the health of both humans and animals and necessitating the development of innovative therapeutic strategies. In this study, we have creatively integrated fatty acids into the previously reported anti-enzymolysis unit (CRKP) in a branched configuration, resulting in the design and fabrication of a series of peptide dendritic with potent antifungal and anti-drug-resistant fungal activities. Notably, peptide dendron C(8)-2 exhibited significantly enhanced antifungal efficacy, favorable in vitro biocompatibility, and remarkable stability in the presence of serum and proteases. Mechanistic investigations reveal that C(8)-2 exert their antifungal effects by increasing cell wall permeability, inducing plasma membrane depolarization, leading to membrane rupture and content release, and generating reactive oxygen species. In addition, peptide dendron C(8)-2 can effectively eliminate Candida albicans from the eyeball in fungal-induced keratitis in mice, and the treatment effect is significantly superior to that of amphotericin B. Consequently, the self-assembled peptide dendron nanoparticles of C(8)-2 hold significant potential as antifungal agents. Additionally, their robust antifungal activity and stability against resistance may effectively address the growing challenge of drug-resistant fungal strains, thereby facilitating the development of future peptide nanoparticle-based therapies.