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Persister cells in human fungal pathogens

Summary

Some fungal infections fail to respond to antifungal drugs even when the fungus should be susceptible to treatment. This happens because certain fungal cells can enter a dormant ‘sleep-like’ state that helps them survive drug exposure. These dormant cells, called persisters, are able to hide from medications by reducing their metabolism and enhancing their protective defenses. Understanding how these persister cells form and survive could lead to better treatments for serious fungal infections.

Background

Invasive fungal diseases cause approximately 3.75 million annual deaths worldwide, yet the antifungal therapeutic arsenal remains limited to three major drug classes. Despite this disease burden, treatment failures occur frequently even with drug-susceptible isolates, suggesting alternative fungal survival strategies beyond classical resistance mechanisms.

Objective

This review systematically integrates recent progress in understanding fungicidal persistence in fungal pathogens, encompassing its conceptual framework, methodologies for evaluation, and underlying molecular mechanisms. The goal is to provide a comprehensive framework to guide future studies and therapeutic development in addressing antifungal persistence.

Results

Antifungal persistence has been observed across diverse fungal pathogens including Candida species and Aspergillus fumigatus. Key mechanisms include cellular dormancy induced by nutrient starvation and biofilm formation, downregulation of ergosterol biosynthesis, and enhanced antioxidant capacity through molecules like ergothioneine and superoxide dismutases. Clinical evidence suggests persistence contributes to treatment failures in both oral candidiasis and aspergillosis.

Conclusion

Fungal persisters represent an underappreciated survival strategy distinct from classical drug resistance that significantly impacts antifungal efficacy and clinical outcomes. Future research should focus on establishing consensus assessment standards, understanding host-drug-fungus interactions, and correlating persister levels with clinical outcomes to develop new therapeutic strategies.
  • Published in:PLoS Pathogens,
  • Study Type:Review,
  • Source: PMID: 41129505, DOI: 10.1371/journal.ppat.1013483
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