Journal article
Mutational analysis of flucytosine resistance in Candida glabrata
Antimicrobial agents and chemotherapy, Vol.54(11), pp.4733-4738
Nov 2010
PMCID: PMC2976130
PMID: 20823283
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The antifungal flucytosine (5-fluorocytosine [5FC]) is a prodrug metabolized to its toxic form, 5-fluorouracil (5FU), only by organisms expressing cytosine deaminase. One such organism is Candida glabrata, which has emerged as the second most common agent of bloodstream and mucosal candidiasis. This emergence has been attributed to the high rate at which C. glabrata develops resistance to azole antifungals. As an oral agent, 5FC represents an attractive alternative or complement to azoles; however, the frequency of 5FC resistance mutations and the mechanisms by which these mutations confer resistance have been explored only minimally. On RPMI 1640 medium containing 1 μg/ml 5FC (32-fold above the MIC, but less than 1/10 of typical serum levels), resistant mutants occurred at a relatively low frequency (2 × 10⁻⁷). Three of six mutants characterized were 5FU cross-resistant, suggesting a mutation downstream of the Fcy1 gene (cytosine deaminase), which was confirmed by sequence analysis of the Fur1 gene (uracil phosphoribosyl transferase). The remaining three mutants had Fcy1 mutations. To ascertain the effects of 5FC resistance mutations on enzyme function, mutants were isolated in ura3 strains. Three of seven mutants harbored Fcy1 mutations and failed to grow in uridine-free, cytosine-supplemented medium, consistent with inactive Fcy1. The remainder grew in this medium and had wild-type Fcy1; further analysis revealed these to be mutated in the Fcy2L homolog of S. cerevisiae Fcy2 (purine-cytosine transporter). Based on this analysis, we characterized three 5FC-resistant clinical isolates, and mutations were identified in Fur1 and Fcy1. These data provide a framework for understanding 5FC resistance in C. glabrata and potentially in other fungal pathogens.
Metrics
13 Record Views
Details
- Title
- Mutational analysis of flucytosine resistance in Candida glabrata
- Creators
- Thomas D Edlind - Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA. tedlind@drexelmed.eduSantosh K Katiyar
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.54(11), pp.4733-4738
- Publisher
- American Society for Microbiology (ASM); United States
- Grant note
- AI073794 / NIAID NIH HHS R01 AI073794 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Identifiers
- 991014878090204721
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy