Introduction

Currently, the high mortality rate of invasive fungal diseases worldwide poses a significant threat to human life and health. However, the antifungal resistance and the blood-brain barrier (BBB) severely limit the treatment options and success rate of clinical management for fungal infections, especially meningitis. Host defense peptides are an ideal class of antibiotic alternatives, but the poor proteolytic stability, difficult synthesis, and expensiveness hinder their applications. It is also difficult to find highly selective antifungal and BBB-penetrating HDP mimics because fungi and mammalian cells are both eukaryotic cells. Inspired by cell-penetrating peptides (CPP), which could penetrate the cell membrane and BBB, we hypothesize that the mimics of both HDP and CPP could penetrate the fungal cell membrane and BBB to realize potent antifungal activity against meningitis.

Methods

A series of guanylated poly(2-oxazoline)s were synthesized by mimicking HDP and CPP. The in vitro and in vivo studies were conducted to realize therapeutic effects against invasive fungal infections and fungal meningitis.

Results

The guanylated poly(2-oxazoline)s PGOx₁₀ displayed efficient and selective antifungal properties against drug-resistant fungi by penetrating the fungal membrane to induce fungal organelle decomposition (Angew. Chem. Int. Ed., 2022, 61, e202200778). PGOx₁₀ also demonstrated potent therapeutic potential in several infection models, including the skin abrasion infection, model, keratitis model, and systemic infection model. By adjusting the side-chain spacers, we found that guanylated poly(2-oxazoline)s PGMeOx₁₀ with methyl spacer group showed more potent antifungal activity, as well as BBB-penetrating property (J. Am. Chem. Soc. 2023, 145, 25753-25765). Therefore, PGMeOx₁₀ displayed anti-infectious activity against fungal meningitis.

Conclusions

This study proposes a novel strategy for designing highly effective and selective antifungal agents and offers potential candidate compounds for combating invasive fungal infections and meningitis.