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Functional Genomic Screening Reveals Core Modulators of Echinocandin Stress Responses in Candida albicans

Tavia Caplan1, Elizabeth J Polvi1, Jinglin L Xie1

  • 1Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada.

Cell Reports
|May 24, 2018
PubMed

Insights

This study reveals how molecular chaperones like Hsp90 and CCT help Candida albicans resist echinocandin antifungal drugs by maintaining cellular stress responses and protein stability, crucial for treating fungal infections.

Area of Science:

  • Medical Mycology
  • Molecular Biology
  • Antimicrobial Resistance

Background:

  • Candida albicans is a major cause of life-threatening fungal infections.
  • Echinocandins are key antifungals targeting cell wall synthesis, but resistance is a growing problem.
  • Drug resistance often involves mutations in the FKS1 gene and cellular stress responses.

Purpose of the Study:

  • To systematically identify genes and pathways involved in Candida albicans' response to echinocandins.
  • To elucidate the role of molecular chaperones in mediating antifungal tolerance and resistance.

Main Methods:

  • Systematic analysis of 3,030 Candida albicans mutants.
  • Investigated the impact of gene deletion or repression on echinocandin susceptibility.
  • Assessed the role of Hsp90 and CCT chaperones in cellular stress responses and drug resistance.

Main Results:

  • Identified 16 genes, including Pkc1-MAPK pathway components, that enhance echinocandin susceptibility when disrupted.
  • Demonstrated that Hsp90 is essential for the stability of Pkc1 and Bck1, mediating echinocandin resistance.
  • Showed that perturbing the CCT chaperonin complex leads to increased echinocandin sensitivity and cell wall defects.

Conclusions:

  • Cellular chaperones, including Hsp90 and CCT, play critical roles in enabling Candida albicans to respond to echinocandin-induced stress.
  • Understanding these chaperone-mediated pathways offers potential new strategies to combat echinocandin resistance in fungal infections.
Keywords:
CCT complexCandida albicansHsp90Pkc1client proteindrug resistanceechinocandinsfunctional genomic screenfungal pathogenstress response

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