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

Summary

This research shows that acidic environments, like those found in inflamed tissues and inside immune cells, make the fungus Cryptococcus neoformans more resistant to the antifungal drug fluconazole. The fungus adapts to acidic conditions by using an alternative iron uptake system that increases the production of protective compounds (ergosterol) in its cell membrane. Understanding this pH-dependent resistance mechanism could help develop better treatment strategies for cryptococcal infections in patients with compromised immune systems.

Background

Cryptococcus neoformans is an opportunistic fungal pathogen causing life-threatening infections in immunocompromised individuals. Environmental pH fluctuations within the host microenvironment play an important role in fungal survival and pathogenesis. Understanding how pH influences antifungal drug susceptibility is crucial for optimizing treatment strategies.

Objective

This study investigated how environmental pH influences antifungal drug susceptibility and iron uptake in C. neoformans, with specific focus on fluconazole resistance mechanisms. The researchers hypothesized that acidic pH alters iron uptake pathways and ergosterol biosynthesis, potentially reducing fluconazole susceptibility.

Results

Acidic conditions (pH 5.0) significantly reduced fluconazole susceptibility compared to neutral pH (pH 7.0). Acidic pH increased intracellular iron accumulation through an alternative iron uptake system independent of the high-affinity Cfo1/Cft1 pathway. Higher intracellular iron led to increased heme and ergosterol production, with upregulation of ERG genes, particularly ERG11.

Conclusion

Environmental acidic pH modulates iron homeostasis and ergosterol biosynthesis in C. neoformans, reducing fluconazole susceptibility. These findings highlight the importance of environmental pH in fungal pathogenesis and suggest that pH-dependent mechanisms should be considered in developing novel antifungal treatment strategies for cryptococcosis.
  • Published in:Journal of Microbiology and Biotechnology,
  • Study Type:Laboratory Research Study,
  • Source: 10.4014/jmb.2504.04007, PMID: 40443228
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