DectiSomes as broad-spectrum antifungal drugs

SUMMARYFungal pathogens represent a significant threat to public health. Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, and Rhizopus delemar are the primary causative agents for aspergillosis, candidiasis, cryptococcosis, and mucormycosis. They and their closest relatives are responsible for more than 94% of fungal disease-related deaths. All four fungal diseases may lead to meningitis, with mortality rates approaching 99%. They are among the WHO-designated priority fungal pathogens needing new and more effective treatments. In response to this therapeutic gap, we developed DectiSomes-drug-loaded liposomes targeted to fungal cells by host-pathogen receptors. Host-pathogen receptors have many advantages over antibodies as liposome-targeting proteins, including a lack of immunogenicity. Of the pathogen receptors we tested, Dectin-1 and Dectin-2 are the most effective targeting proteins against the fungal pathogens tested. Liposomes loaded with amphotericin B and coated with one of these pathogen receptors bind specifically and strongly to the four pathogens and kill them, reducing the effective dose of amphotericin B by more than an order of magnitude over the untargeted control. DectiSomes are also more effective in murine models of fungal infection. Furthermore, we developed small, malleable versions of DectiSomes with improved drug delivery to the brain and are more effective against cryptococcal meningitis, holding promise for treating all forms of fungal meningitis. Herein, we review our progress and discuss the potential of DectiSomes as a new and effective targeted delivery system for antifungal drugs. In addition, we discuss the challenges associated with fungal diseases and the roadblocks to antifungal drug development and medical mycology research.