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Mode of Action of 5-Fluorocytosine and Mechanisms of Resistance
Abstract
Mode of action of 5-fluorocytosine (5-FC) and mechanisms of resistance to the drug are discussed on the basis of experiments performed with Candida albicans ATCC 26790 and with 50 selected clinical isolates of C. albicans belonging to serological type A or B and representing various degrees and models of 5-FC resistance (sensitivity). Incorporation of 5-fluorouridylic acid into RNA appeared as a prerequisite to antifungal activity, although at a given incorporation rate, growth inhibition varied considerably from one strain to the other. The amino acid pool was unbalanced, and there was evidence for disturbance of protein synthesis. These dysfunctions of RNA probably account for growth inhibition and cell death, whereas up to the present, there was no proof of formation of 5-fluorodeoxyuridylic acid nor of subsequent inhibition of thymidylate synthetase. Incorporation of fluorinated pyrimidine into RNA was lower in normally sensitive type B strains than in normally sensitive ones of type A, whereas the frequency of 5-FC-resistant mutants was the same. The two serological types did not differ in the activity of cytosine permease nor in that of cytosine deaminase. Among 29 clinical isolates with 5-FC resistance (or impaired sensitivity) no instance of cytosine permease deficiency was found. Two isolates (belonging to the serological type A) were deficient in cytosine deaminase, whereas the majority was probably deficient in uridine monophosphate pyrophosphorylase or had a surplus of de novo synthesis of pyrimidines. Relative 5-FC resistance was more common than complete resistance.
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Baracaldo-Santamaría, D., Cala-García, J., Medina-Rincón, G. J., Rojas-Rodríguez, L. C., & Calderón‐Ospina, C. (2022) · Antibiotics · doi:10.3390/antibiotics11050645 · Cited by 35
“It should be noted that 5-fluorouracil is highly toxic to human and non-human mammalian cells and is not readily taken up by fungal cells, thus leaving it ineffective as an antifungal agent; instead, its main current use concerns the treatment of certain types of cancer, mainly colorectal carcinoma [152,153].”
BackgroundSynthesis andin vivodiuretic activity of some novel pyrimidine derivatives
Majeed, J., & Yar, M. S. (2011) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.3109/14756366.2011.557022 · Cited by 30
Chemotherapy of Systemic Fungal Diseases
Hoeprich, P. D. (1978) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pa.18.040178.001225 · Cited by 30
Resistance to Systemic Antifungal Agents
Scholer, H. J., & Polak, A. (1984) · Elsevier eBooks · doi:10.1016/b978-0-12-138120-2.50019-8 · Cited by 30
Self-citationTreatment of severe chromoblastomycosis with itraconazole and 5-flucytosine association
Antonello, V. S., da Silva, M. C. A., Cambruzzi, E., Kliemann, D. A., Santos, B. R., & Queiroz‐Telles, F. (2010) · Revista do Instituto de Medicina Tropical de São Paulo · doi:10.1590/s0036-46652010000600008 · Cited by 29
Gubbins, P. O., & Anaissie, E. J. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-5680-5.00007-4 · Cited by 29
Chavan, P. N., Bangale, S., Pansare, D. N., Shelke, R. N., Jadhav, S., Tupare, S., Kamble, D. P., & Rai, M. (2020) · Journal of Heterocyclic Chemistry · doi:10.1002/jhet.4048 · Cited by 28
Topical and systemic antifungals in dermatology practice
Durdu, M., İlkit, M., Tamaddon, Y., Tolooe, A., Rafati, H., & Seyedmousavi, S. (2016) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2017.1263564 · Cited by 28
Antifungal Susceptibility Testing of Yeasts
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El‐Sayed, A. S. A., Mohamed, N. Z., Yassin, M. A., Amer, M. M., El-Sharkawy, R. M., Elsayed, N., & Ali, M. G. (2022) · Heliyon · doi:10.1016/j.heliyon.2022.e10660 · Cited by 27
Candida: A Causative Agent of an Emerging Infection
Ghannoum, M. A. (2001) · Journal of Investigative Dermatology Symposium Proceedings · doi:10.1046/j.0022-202x.2001.00047.x · Cited by 27
“Subsequently, 5-FU is converted by UMP pyrophosphorylase into 5-fluorouridylic acid, which is further phosphorylated and incorporated into RNA, resulting in disruption of protein synthesis”
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“Some of the pyrimidine analogues (2) (Agarwal et al., 2002), and (3) (Polak and Scholer, 1975) have been reported as potential antimicrobial agents.”
BackgroundMcManus, B. A., Moran, G. P., Higgins, J., Sullivan, D. J., & Coleman, D. C. (2009) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00607-09 · Cited by 24
“1), leading to the depletion of dTTP and the misincorporation of dUTP into newly synthesized DNA, causing irreversible DNA damage and cell cycle arrest (14, 31, 41).”
BackgroundInfluential
Metadata
- Authors
- Polak, A., & Scholer, H. J.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- ORCID
- Polak, Annemarie
- Venue
- Chemotherapy
- Publisher
- S. Karger AG
- Published
- 2009-05-25
- Volume
- 21
- Issue
- 3-4
- Pages
- 113-130
- ISSN
- 0009-3157 (ISSN-L)
- 1421-9794
- OpenAlex
- W2072785474
- Cited by
- 250
- References
- 0
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 10 · 2023: 12 · 2022: 7 · 2021: 6 · 2020: 10 · 2019: 7 · 2018: 7 · 2017: 4 · 2016: 5 · 2015: 2 · 2014: 8 · 2013: 4 · 2012: 6
- FWCI
- 7.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemotherapy (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- 5-fluorocytosine, Candida albicans, antifungal resistance, mechanism of action, cytosine deaminase, protein synthesis inhibition, clinical isolates
- MeSH terms
- Candida albicans, Cell Division, Cytidine Deaminase, Cytosine, Drug Resistance, Microbial, Flucytosine, RNA, Serotyping, Uracil Nucleotides, Membrane Transport Proteins
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