Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 145, Issue 47, Pages 25753-25765Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.3c09240
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In this study, we designed and synthesized a novel antifungal polymer that showed promising efficacy against drug-resistant fungi and biofilm. The polymer also demonstrated the potential to treat meningitis by breaking through the blood-brain barrier. This research provides a new strategy for the design of effective antifungal agents.
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, PGMeOx(10) bearing a methylene spacer arm, displays potent activities against the drug-resistant fungi and biofilm, negligible toxicity, and insusceptibility to antimicrobial resistance. Moreover, PGMeOx(10) can break BBB retractions to exert promising antifungal functions in the brain. PGMeOx(10) demonstrates potent in vivo antifungal therapeutic efficacy in mouse models including skin infection, systemic infections, and meningitis. PGMeOx(10) 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.
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