Effective combinatorial antifungal therapy using a host defense peptide mimic that self-assembles into delivery...

The synergistic combination of two antimicrobial drugs is a promising therapeutic modality for many infectious diseases. However, systemic fungal infections still have a high mortality rate because of distinct in vivo distributions of the two drugs. Here we address this challenge by designing an antifungal polymer that forms micelles suitable for delivering a second antifungal agent to achieve temporal and spatial consistency of delivery. We show that the polymer, which mimics host defense peptides, exerts a synergistic effect with the antifungal amphotericin B (AmB). The AmB-encapsulated micelles (AmBmicelles) greatly reduce the toxicity of AmB through slow release and expand its therapeutic window in vivo. AmBmicelles can selectively target fungal pathogens through charge interactions with the fungal membrane. In mouse models of systemic candidiasis and cryptococcal meningitis, AmBmicelles increase the survival rate by 67-100% compared to the state-of-the-art drug AmBisome or AmBisome and 5-flucytosine combination, suggesting that the strategy may be effective in combating drug-resistant fungal infections including meningitis.