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Updated: Jul 5, 2025
High-throughput Screening of Chemical Compounds to Elucidate Their Effects on Bacterial Persistence
Published on: February 23, 2021
Fungicide-tolerant persister formation during cryptococcal pulmonary infection
Weixin Ke1, Yuyan Xie2, Yingying Chen2
1State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Abstract:
Bacterial persisters, a subpopulation of genetically susceptible cells that are normally dormant and tolerant to bactericides, have been studied extensively because of their clinical importance. In comparison, much less is known about the determinants underlying fungicide-tolerant fungal persister formation in vivo. Here, we report that during mouse lung infection, Cryptococcus neoformans forms persisters that are highly tolerant to amphotericin B (AmB), the standard of care for treating cryptococcosis. By exploring stationary-phase indicator molecules and developing single-cell tracking strategies, we show that in the lung, AmB persisters are enriched in cryptococcal cells that abundantly produce stationary-phase molecules. The antioxidant ergothioneine plays a specific and key role in AmB persistence, which is conserved in phylogenetically distant fungi. Furthermore, the antidepressant sertraline (SRT) shows potent activity specifically against cryptococcal AmB persisters. Our results provide evidence for and the determinant of AmB-tolerant persister formation in pulmonary cryptococcosis, which has potential clinical significance.
Insights
Fungal persisters in lung infections show high tolerance to amphotericin B. The antioxidant ergothioneine and stationary-phase molecules are key to this persistence, with sertraline showing potential against these tolerant cells.
Area of Science:
- Medical Mycology
- Antimicrobial Resistance
- Fungal Pathogenesis
Background:
- Bacterial persisters are well-studied dormant cells tolerant to antibiotics.
- Fungal persister formation and its determinants, especially in vivo, are less understood.
- Cryptococcus neoformans causes cryptococcosis, a serious fungal lung infection.
Purpose of the Study:
- Investigate the formation and determinants of fungicide-tolerant fungal persisters in vivo.
- Identify mechanisms of amphotericin B (AmB) tolerance in Cryptococcus neoformans during lung infection.
- Explore potential therapeutic strategies against AmB-tolerant fungal persisters.
Main Methods:
- Mouse lung infection model with Cryptococcus neoformans.
- Single-cell tracking strategies to monitor fungal cell behavior.
- Analysis of stationary-phase indicator molecules and antioxidant roles.
- In vitro drug screening against fungal persisters.
Main Results:
- Cryptococcus neoformans forms AmB-tolerant persisters during mouse lung infection.
- AmB persisters are enriched in cells producing abundant stationary-phase molecules.
- The antioxidant ergothioneine is crucial for AmB persistence in C. neoformans and other fungi.
- The antidepressant sertraline (SRT) effectively targets cryptococcal AmB persisters.
Conclusions:
- Ergothioneine and stationary-phase molecules are key determinants of AmB-tolerant persister formation in pulmonary cryptococcosis.
- Sertraline demonstrates specific activity against fungal AmB persisters, suggesting a novel therapeutic approach.
- Understanding fungal persister biology is critical for developing effective treatments against life-threatening fungal infections.
