Moderate levels of 5-fluorocytosine cause the emergence of high frequency resistance in cryptococci
| العنوان: | Moderate levels of 5-fluorocytosine cause the emergence of high frequency resistance in cryptococci |
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| المؤلفون: | Hongyi Cai, Ami Khanal Lamichhane, Kyung J. Kwon-Chung, Peter Walter, Yun C. Chang, John E. Bennett |
| المصدر: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-13 (2021) |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Science, 030106 microbiology, Mutant, Gene Dosage, Intracellular Space, Cryptococcus, Flucytosine, General Physics and Astronomy, Microbial Sensitivity Tests, Drug resistance, Antimicrobial resistance, Article, General Biochemistry, Genetics and Molecular Biology, Microbiology, Fungal Proteins, 03 medical and health sciences, Antibiotic resistance, Fungal genetics, Drug Resistance, Fungal, Gene Duplication, Gene Expression Regulation, Fungal, Genes, Suppressor, Antifungal agents, Gene, chemistry.chemical_classification, Multidisciplinary, biology, Permease, Genetic Variation, Reproducibility of Results, General Chemistry, biology.organism_classification, Clone Cells, 030104 developmental biology, Enzyme, chemistry, Mutation, Uridine Diphosphate Glucuronic Acid, Chromosomes, Fungal, Genome, Fungal |
| الوصف: | The antifungal agent 5-fluorocytosine (5-FC) is used for the treatment of several mycoses, but is unsuitable for monotherapy due to the rapid development of resistance. Here, we show that cryptococci develop resistance to 5-FC at a high frequency when exposed to concentrations several fold above the minimal inhibitory concentration. The genomes of resistant clones contain alterations in genes relevant as well as irrelevant for 5-FC resistance, suggesting that 5-FC may be mutagenic at moderate concentrations. Mutations in FCY2 (encoding a known permease for 5-FC uptake), FCY1, FUR1, UXS1 (encoding an enzyme that converts UDP-glucuronic acid to UDP-xylose) and URA6 contribute to 5-FC resistance. The uxs1 mutants accumulate UDP-glucuronic acid, which appears to down-regulate expression of permease FCY2 and reduce cellular uptake of the drug. Additional mutations in genes known to be required for UDP-glucuronic acid synthesis (UGD1) or a transcriptional factor NRG1 suppress UDP-glucuronic acid accumulation and 5-FC resistance in the uxs1 mutants. Pathogenic fungi rapidly develop resistance to the antifungal agent 5-fluorocytosine (5-FC). Here, Chang et al. explore the mechanisms by which Cryptococcus develops 5-FC resistance at a high frequency, including mutations in several genes and altered levels of key metabolites. |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6a4da524d6801f9c09c5b078f8a006bc https://doi.org/10.1038/s41467-021-23745-1 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....6a4da524d6801f9c09c5b078f8a006bc |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 20411723 |
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