Calcineurin is required for Candida glabrata Pdr1 transcriptional activation

• Published in: mBio Vol. 14; no. 6; p. e0241623
• Main Authors: Vu, Bao Gia, Simonicova, Lucia, Moye-Rowley, W Scott
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 19.12.2023
• Subjects: antifungal resistance; Antimicrobial Chemotherapy; Candida glabrata; fluconazole; Observation; Pdr1; transcriptional regulation; fluconazole; Candida glabrata; Pdr1; transcriptional regulation; antifungal resistance
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.02416-23

Fluconazole is one of the most commonly used antifungals today. A result of this has been the inevitable selection of fluconazole-resistant organisms. This is an especially acute problem in the pathogenic yeast . Elevated minimal inhibitory concentrations for fluconazole in are frequently associated with substitution mutations within the Zn2Cys6 zinc cluster-containing transcription factor-encoding gene . These mutant Pdr1 regulators drive constitutively high expression of target genes like that encodes an ATP-binding cassette transporter thought to act as a drug efflux pump. Exposure of to fluconazole induced expression of both Pdr1 and , although little is known of the molecular basis underlying the upstream signals that trigger Pdr1 activation. Here, we show that the protein phosphatase calcineurin is required for fluconazole-dependent induction of Pdr1 transcriptional regulation. Calcineurin catalytic activity is required for normal Pdr1 regulation, and a hyperactive form of this phosphatase can decrease susceptibility to the echinocandin caspofungin but does not show a similar change for fluconazole susceptibility. Loss of calcineurin from strains expressing two different gain-of-function forms of Pdr1 also caused a decrease in expression and increased fluconazole susceptibility, demonstrating that even these hyperactive Pdr1 regulatory mutants cannot bypass the requirement for calcineurin. Our data implicate calcineurin activity as a link tying azole and echinocandin susceptibility together via the control of transcription factor activity.IMPORTANCEDrug-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 , 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 .