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

ABSTRACT: The opportunistic fungal pathogen Cryptococcus neoformans faces a wide range of environmental pH within the host, and adaptation to different pH conditions plays a critical role in their survival and pathogenesis. In the current study, how environmental pH influences antifungal susceptibility and iron uptake in C. neoformans was investigated. We found that acidic pH conditions significantly reduced antifungal susceptibility of C. neoformans to fluconazole. Moreover, our study revealed that iron acquisition in C. neoformans at acidic pH is independent of the high-affinity iron uptake system, and leads to increase of intracellular iron accumulation, increased ergosterol and heme levels, which may contribute to reduced fluconazole susceptibility of the fungus. Transcriptome analysis further elucidated the molecular mechanisms underlying the pH-dependent shift of iron uptake and antifungal susceptibility of C. neoformans. Our findings highlight the importance of environmental pH in physiology and pathogenesis of C. neoformans and provide insights into developing novel treatment for cryptococcosis.

ORGANISM(S): Cryptococcus neoformans var. grubii H99

PROVIDER: GSE291861 | GEO | 2025/03/18

REPOSITORIES: GEO

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Project description:Azole antifungal agents such as fluconazole exhibit fungistatic activity against Candida albicans. Strategies to enhance azole antifungal activity would be therapeutically appealing. In an effort to identify transcriptional pathways that influence fluconazole susceptibility, we sought to identify transcription factors (TFs) involved in this process. From a collection of C. albicans strains disrupted for genes encoding TFs (Homann et al., PLoS Genet. 2009;5:e1000783), four exhibited a marked reduction in minimum fungicidal concentration (MFC) in both RPMI and YPD media. One of these, UPC2, has been previously characterized with regard to its role in azole susceptibility. Of mutants representing the three remaining TF genes of interest, one (CAS5) was unable to recover from fluconazole exposure at concentrations as low as 2 M-BM-5g/mL after 72 hours in YPD medium. This mutant also showed reduced susceptibility and a clear zone of inhibition by Etest, was unable to grow on solid media containing 10 M-BM-5g/mL fluconazole, and exhibited increased susceptibility by time-kill analysis. CAS5 disruption in highly azole-resistant clinical isolates exhibiting multiple resistance mechanisms did not alter susceptibility. However, CAS5 disruption in strains with specific resistance mutations in ergosterol biosynthesis or efflux pumps resulted in a moderate reduction in MIC and MFC. Genome-wide transcriptional analysis was performed in the presence of fluconazole and was consistent with the suggested role of CAS5 in cell wall organization while also suggesting a role in iron transport and homeostasis. These findings suggest that Cas5 regulates a transcriptional network that influences susceptibility of C. albicans to fluconazole. Further delineation of this transcriptional network may identify targets for potential co-therapeutic strategies to enhance the activity to the azole class of antifungals. We examined the genome-wide gene expression profiles of the wild-type parent strain SC5314 and its cas5M-NM-^T/M-NM-^T derivative in response to fluconazole in order to identify genes whose expression in response to fluconazole is influenced by Cas5.

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

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