ArticleMedical mycology2018
Flucytosine resistance in Cryptococcus gattii is indirectly mediated by the FCY2-FCY1-FUR1 pathway.
Article in Medical mycology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 20 citations in OpenAlex.
- RapidmSphere · 2025Article
- Genetic mutations in Cryptococcus neoformans pyrimidine salvage pathway enzymes contribute to reduced susceptibility against 5-fluorocytosine.npj antimicrobials and resistance · 2024Article
- Factors Influencing the Nitrogen-Source Dependent Flucytosine Resistance in Cryptococcus Species.mBio · 2023Article
- Molecular mechanisms of acquired antifungal drug resistance in principal fungal pathogens and EUCAST guidance for their laboratory detection and clinical implications.The Journal of antimicrobial chemotherapy · 2022Review
- Molecular Epidemiology and Antifungal Resistance ofFrontiers in microbiology · 2022Article
- Molecular Mechanisms of 5-Fluorocytosine Resistance in Yeasts and Filamentous Fungi.Journal of fungi (Basel, Switzerland) · 2021Review
- Moderate levels of 5-fluorocytosine cause the emergence of high frequency resistance in cryptococci.Nature communications · 2021Article
- The Antifungal Activity of HMA, an Amiloride Analog and Inhibitor of NaFrontiers in microbiology · 2021Article
- Review
- 5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus.Nature communications · 2020Article
- Flucytosine and its clinical usage.Therapeutic advances in infectious diseaseReview
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
Abstract
Cryptococcosis is an opportunistic fungal infection caused by members of the two sibling species complexes: Cryptococcus neoformans and Cryptococcus gattii. Flucytosine (5FC) is one of the most widely used antifungals against Cryptococcus spp., yet very few studies have looked at the molecular mechanisms responsible for 5FC resistance in this pathogen. In this study, we examined 11 C. gattii clinical isolates of the major molecular type VGIII based on differential 5FC susceptibility and asked whether there were genomic changes in the key genes involved in flucytosine metabolism. Susceptibility assays and sequencing analysis revealed an association between a point mutation in the cytosine deaminase gene (FCY1) and 5FC resistance in two of the studied 5FC resistant C. gattii VGIII clinical isolates, B9322 and JS5. This mutation results in the replacement of arginine for histidine at position 29 and occurs within a variable stretch of amino acids. Heterologous expression of FCY1 and spot sensitivity assays, however, demonstrated that this point mutation did not have any effect on FCY1 activities and was not responsible for 5FC resistance. Comparative sequence analysis further showed that no changes in the amino acid sequence and no genomic alterations were observed within 1 kb of the upstream and downstream sequences of either cytosine permeases (FCY2-4) or uracil phosphoribosyltransferase (FUR1) genes in 5FC resistant and 5FC susceptible C. gattii VGIII isolates. The herein obtained results suggest that the observed 5FC resistance in the isolates B9322 and JS5 is due to changes in unknown protein(s) or pathway(s) that regulate flucytosine metabolism.
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