Peptide-Mimicking Poly(2-oxazoline)s Possessing Potent Antifungal Activity and BBB Penetrating Property to Treat Invasive Infections and Meningitis

Invasive fungal infections, including meningitis, cause a high mortality rate due to few available antifungal drugs and frequently associated side effects and quick emergence of drug-resistant fungi. The restrictive permeability of the blood-brain barrier (BBB) further limits the efficacy of antifungal agents substantially in treating meningitis. Hereby, we design and synthesize guanidinium-functionalized poly(2-oxazoline)s by mimicking cell-penetrating peptides. The optimal polymer, PGMeOx₁₀ bearing a methylene spacer arm, displays potent activities against the drug-resistant fungi and biofilm, negligible toxicity, and insusceptibility to antimicrobial resistance. Moreover, PGMeOx₁₀ can break BBB retractions to exert promising antifungal functions in the brain. PGMeOx₁₀ demonstrates potent in vivo antifungal therapeutic efficacy in mouse models including skin infection, systemic infections, and meningitis. PGMeOx₁₀ effectively rescues infected mice and reduces fungal burden and inflammation in the brain. These results and the excellent biosafety of poly(2-oxazoline)s indicate the effectiveness and potential of our strategy to design promising antifungal agents in treating systemic infections and meningitis.