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Moderate levels of 5-fluorocytosine cause the emergence of high frequency resistance in cryptococci

Author

Listed:
  • Yun C. Chang

    (Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Ami Khanal Lamichhane

    (Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Hongyi Cai

    (Clinical Mass Spectrometry Core, NIDDK, NIH)

  • Peter J. Walter

    (Clinical Mass Spectrometry Core, NIDDK, NIH)

  • John E. Bennett

    (Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

  • Kyung J. Kwon-Chung

    (Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH)

Abstract

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.

Suggested Citation

  • Yun C. Chang & Ami Khanal Lamichhane & Hongyi Cai & Peter J. Walter & John E. Bennett & Kyung J. Kwon-Chung, 2021. "Moderate levels of 5-fluorocytosine cause the emergence of high frequency resistance in cryptococci," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23745-1
    DOI: 10.1038/s41467-021-23745-1
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