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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.