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Updated: Jul 11, 2025
Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance
Published on: December 28, 2017
Calcineurin is required for Candida glabrata Pdr1 transcriptional activation
Bao Gia Vu1, Lucia Simonicova1, W Scott Moye-Rowley1
1Department of Molecular Physiology and Biophysics, Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.
Importance:
Drug-resistant microorganisms are a problem in the treatment of all infectious diseases; this is an especially acute problem with fungi due to the existence of only three major classes of antifungal drugs, including the azole drug fluconazole. In the pathogenic yeast Candida glabrata, mutant forms of a transcription factor called Pdr1 are commonly associated with decreased fluconazole susceptibility and poor clinical outcomes. Here, we identify a protein phosphatase called calcineurin that is required for fluconazole-dependent induction of Pdr1 transcriptional activation and associated drug susceptibility. Gain-of-function mutant forms of Pdr1 still required the presence of calcineurin to confer normally decreased fluconazole susceptibility. Previous studies showed that calcineurin controls susceptibility to the echinocandin class of antifungal drugs, and our data demonstrate that this protein phosphatase is also required for normal azole drug susceptibility. Calcineurin plays a central role in susceptibility to two of the three major classes of antifungal drugs in C. glabrata.
Insights
Calcineurin is essential for the antifungal drug fluconazole to activate the Pdr1 transcription factor in Candida glabrata. This protein phosphatase is crucial for azole drug susceptibility in this pathogenic yeast.
Area of Science:
- Mycology
- Molecular Biology
- Drug Discovery
Background:
- Antifungal drug resistance is a significant clinical challenge, particularly in pathogenic fungi like Candida glabrata.
- Limited antifungal drug classes, including azoles like fluconazole, exacerbate treatment difficulties.
- Mutant Pdr1 transcription factors are linked to reduced fluconazole susceptibility and poor patient outcomes in C. glabrata.
Purpose of the Study:
- To investigate the role of calcineurin in the transcriptional activation of Pdr1 in response to fluconazole.
- To determine calcineurin's requirement for azole drug susceptibility in Candida glabrata.
- To elucidate calcineurin's broader role in antifungal drug susceptibility.
Main Methods:
- Genetic analysis of Candida glabrata strains.
- Assays for Pdr1 transcriptional activation.
- Measurement of fluconazole susceptibility.
Main Results:
- Calcineurin is indispensable for fluconazole-induced Pdr1 transcriptional activation.
- Calcineurin is required for gain-of-function Pdr1 mutants to confer reduced fluconazole susceptibility.
- Calcineurin is essential for normal azole drug susceptibility in C. glabrata.
Conclusions:
- Calcineurin plays a critical role in regulating susceptibility to azole antifungal drugs in C. glabrata.
- This protein phosphatase is central to the mechanism of action for two major classes of antifungal drugs in this pathogen.
- Targeting calcineurin may offer a strategy to overcome drug resistance in fungal infections.
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