Seminar: New Potential Antifungal Targets of Cryptococcus Neoformans

Abstract: Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening meningoencephalitis, particularly in immunocompromised individuals. Current antifungal treatments are limited and often ineffective due to drug toxicity and emerging of drug resistance. The phosphate (PHO) signaling pathway is critical for fungal survival and virulence, regulating phosphate homeostasis and enabling adaptation to nutrient-limited host environments. In C. neoformans, disruption of high-affinity phosphate transporters impairs virulent traits such as capsule formation, melanin production, and survival in macrophages. Notably, the phosphate transporter mutants exhibited increased sensitivity to caspofungin, an echinocandin that targets β-glucan in the cell wall but is generally ineffective against C. neoformans. Further investigation revealed that the endoplasmic reticulum (ER) stress inducer tunicamycin synergistically enhanced caspofungin sensitivity and impaired capsule formation, likely due to disruption of cell wall structure. These findings suggest that phosphate signaling supports ER function, which in turn maintains cell wall and capsule integrity, contributing to antifungal resistance. Our work identifies a potential novel therapeutic strategy: combining ER stress inducers with echinocandins to overcome intrinsic drug resistance in C. neoformans. Targeting pathways related to phosphate acquisition and the ER may provide a promising avenue for developing more effective antifungal therapies.