Mechanistic Basis of pH-Dependent 5-Flucytosine Resistance in Aspergillus fumigatus.

TitleMechanistic Basis of pH-Dependent 5-Flucytosine Resistance in Aspergillus fumigatus.
Publication TypeJournal Article
Year of Publication2018
AuthorsGsaller, F, Furukawa, T, Carr, PD, Rash, B, Jöchl, C, Bertuzzi, M, Bignell, EM, Bromley, MJ
JournalAntimicrob Agents Chemother
Volume62
Issue6
Date Published2018 Jun
ISSN1098-6596
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 infection. Despite being potent against other fungal pathogens, 5FC has limited activity against when standard assays are used to determine susceptibility. However, in modified assays where the pH is set to pH 5, the activity of 5FC increases significantly. Here we provide evidence that , 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 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 expression, such as PacC or other components of the pH-sensing machinery.

DOI10.1128/AAC.02593-17
Alternate JournalAntimicrob. Agents Chemother.
PubMed ID29610197
PubMed Central IDPMC5971587