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

Yun C. Chang (), Ami Khanal Lamichhane, Hongyi Cai, Peter J. Walter, John E. Bennett and Kyung J. Kwon-Chung
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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

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23745-1

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