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The antifungal mechanism of EntV-derived peptides is associated with a reduction in extracellular vesicle release

Summary

Researchers discovered that a small peptide derived from a bacterium called EntV can fight Candida fungal infections by targeting specialized vesicles (tiny sacs) that fungi use to spread infections. Unlike traditional antifungal drugs that kill fungi, EntV works by blocking the release of these vesicles, reducing the fungus’s ability to infect and form protective biofilms. This new approach could lead to treatments that work against drug-resistant fungi without the toxicity issues of current antifungals.

Background

Candida albicans is an opportunistic fungal pathogen causing systemic and superficial infections, particularly in immunocompromised patients. Treatment is complicated by limited antifungal options and emerging drug resistance. Previous work demonstrated the efficacy of EntV, a bacteriocin-derived peptide, against C. albicans infection in various animal models without fungicidal or fungistatic activity.

Objective

To identify the molecular mechanism of action by which EntV-derived peptides exert antifungal effects and inhibit fungal virulence. The study aimed to characterize how the 12-amino acid EntV peptide reduces C. albicans adhesion and biofilm formation without directly killing fungal cells.

Results

EntV peptides bind to fungal cell surfaces in a punctate and dynamic manner, colocalizing with extracellular vesicles (EVs). Transcriptomic and genetic analyses linked this activity to the ESCRT pathway involved in vesicular trafficking. Treatment with EntV significantly reduced EV secretion and increased EV size heterogeneity, with ESCRT pathway mutants showing altered susceptibility to the peptide.

Conclusion

EntV-derived peptides exert antifungal effects through inhibition of extracellular vesicle-mediated virulence rather than direct fungicidal activity. This novel anti-virulence mechanism targeting EVs provides a promising strategy for developing therapeutics against drug-resistant fungal pathogens. EVs represent a druggable target for future antifungal compound development.
  • Published in:PLoS Pathogens,
  • Study Type:Experimental Research Study,
  • Source: PMID: 40982534, DOI: 10.1371/journal.ppat.1013519
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