Long-chain 4-aminoquinolines inhibit filamentation and increase efficacy of nystatin against Candida albicans infections in vivo

In exploring a growing demand for innovative approaches to tackle emerging and life threatening fungal diseases, we identified long-chain 4-aminoquinoline (4-AQ) derivatives as a new class of anti-virulence agents. For the first time, we demonstrated that 4-AQs effectively prevent filamentation of Candida albicans, a key virulence trait, under multiple triggering conditions. Selected 4-AQ derivatives inhibited filament formation in a zebrafish model of disseminated candidiasis at 1.56 µM, with no toxicity up to 50 µM. Combining nystatin with 4-AQs resulted in a 100% survival rate of infected embryos and complete eradication of C. albicans, compared to 65-75% survival with nystatin alone. The most potent 4-AQ derivatives also showed significant activity against C. albicans biofilms, with derivative 11 suppressing mixed C. albicans-Pseudomonas aeruginosa biofilms. This dual capability highlights the potential of 4-AQs as novel anti-virulence agents to enhance conventional antifungal therapies, marking a significant advance in treating complex fungal infections.