The mechanistic basis of pH-dependent 5-flucytosine resistance in Aspergillus fumigatus

Research output: Contribution to journalArticle

  • External authors:
  • Fabio Gsaller
  • Paul D. Carr
  • Bharatkumar Rash
  • Christoph Jöchl

Abstract

The antifungal drug 5-flucytosine (5FC), a derivative of the nucleobase cytosine, is licensed for the treatment of fungal diseases; however, it is rarely used as a monotherapeutic to treat Aspergillus infection. Despite being potent against other fungal pathogens, 5FC has limited activity against Aspergillus fumigatus when standard in vitro assays are used to determine susceptibility. However, in modified in vitro assays where the pH is set to pH 5, the activity of 5FC increases significantly. Here we provide evidence that fcyB, a gene that encodes a purine-cytosine permease orthologous to known 5FC importers, is downregulated at pH 7 and is the primary factor responsible for the low efficacy of 5FC at pH 7. We also uncover two transcriptional regulators that are responsible for the repression of fcyB and, consequently, mediators of 5FC resistance, the CCAAT binding complex (CBC) and the pH regulatory protein PacC. We propose that the activity of 5FC might be enhanced by the perturbation of factors that repress fcyB expression, such as PacC or other components of the pH-sensing machinery.

Bibliographical metadata

Original languageEnglish
Pages (from-to)e02593-17
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number6
Early online date2 Apr 2018
DOIs
Publication statusPublished - Jun 2018