Calcineurin is required for Candida glabrata Pdr1 transcriptional activation

mBio. 2023 Dec 19;14(6):e0241623. doi: 10.1128/mbio.02416-23. Epub 2023 Nov 9.

Abstract

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.

Keywords: Candida glabrata; Pdr1; antifungal resistance; fluconazole; transcriptional regulation.

MeSH terms

  • Antifungal Agents* / pharmacology
  • Calcineurin* / genetics
  • Calcineurin* / metabolism
  • Candida glabrata* / drug effects
  • Candida glabrata* / genetics
  • Candida glabrata* / metabolism
  • Drug Resistance, Fungal* / genetics
  • Fluconazole* / pharmacology
  • Fungal Proteins* / genetics
  • Fungal Proteins* / metabolism
  • Gene Expression Regulation, Fungal* / drug effects
  • Microbial Sensitivity Tests
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Activation*

Substances

  • Calcineurin
  • Antifungal Agents
  • Fluconazole
  • Fungal Proteins
  • Transcription Factors