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The Toxicity of a Novel Antifungal Compound Is Modulated by Endoplasmic Reticulum-Associated Protein Degradation

Shriya Raj1, Karthik Krishnan2, David S Askew2

  • 1Institut Pasteur, Unité des Aspergillus, Département Mycologie, Paris, France.

Antimicrobial Agents and Chemotherapy
|December 16, 2015
PubMed

Insights

A new antifungal compound, sr7575, effectively inhibits fungal growth by disrupting endoplasmic reticulum-associated protein degradation (ERAD). This discovery offers a novel strategy for developing antifungal drugs targeting fungal protein quality control mechanisms.

Area of Science:

  • Mycology
  • Molecular Biology
  • Drug Discovery

Background:

  • Antifungal drug development faces challenges due to limited targets and emerging resistance.
  • Identifying novel mechanisms of fungal growth inhibition is crucial for new therapeutic strategies.

Purpose of the Study:

  • To discover new antifungal compounds with novel mechanisms of action.
  • To investigate the molecular targets and pathways affected by a newly identified antifungal agent, sr7575.

Main Methods:

  • Chemical screening of 4,454 compounds against Aspergillus fumigatus to identify antifungal activity.
  • Chemogenomic analysis using Saccharomyces cerevisiae deletion and DAmP mutant libraries to determine sr7575's mode of action.
  • Comparative analysis with existing chemogenomic data to identify sensitive pathways.

Main Results:

  • The compound sr7575 demonstrated broad-spectrum antifungal activity against multiple fungal species (A. fumigatus, C. neoformans, C. albicans, S. cerevisiae) with no observed mammalian cell toxicity.
  • Chemogenomic screening revealed that sr7575 specifically targets the endoplasmic reticulum-associated protein degradation (ERAD) pathway and the ER membrane protein complex (EMC).
  • ERAD-deficient mutants showed hypersensitivity to sr7575, confirming ERAD's role in sensitivity and indicating a conserved mechanism across fungal types.

Conclusions:

  • Sr7575 exerts antifungal effects by disrupting fungal protein quality control through the ERAD pathway, independent of the unfolded protein response (UPR).
  • The ERAD pathway represents a specific vulnerability in fungal organisms, presenting a promising target for the development of novel antifungal therapies.

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