Acidic pH Reduces Fluconazole Susceptibility in Cryptococcus neoformans by Altering Iron Uptake and Enhancing Ergosterol Biosynthesis.

The opportunistic fungal pathogen Cryptococcus neoformans encounters diverse environmental pH conditions within the host. Hence, the ability to adapt to different pH levels plays a key role in survival and pathogenesis, although a full understanding of adaptation has yet to be achieved. In this study, we investigated how environmental pH influences antifungal drug susceptibility and iron uptake in C. neoformans. We found that acidic conditions significantly reduced the susceptibility of C. neoformans to the antifungal drug fluconazole. Moreover, iron acquisition in C. neoformans was independent of the high-affinity iron uptake system under acidic conditions, and lower pH increased the levels of intracellular iron, ergosterol, and heme, potentially accounting for the reduced susceptibility of the fungus to fluconazole. Transcriptome analysis further elucidated the mechanisms underlying the pH-dependent shift in iron uptake and antifungal susceptibility in C. neoformans. Overall, our findings highlight the importance of environmental pH in the physiology and pathogenesis of C. neoformans and provide insights to support the development of novel treatments for cryptococcosis.