Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.
Clinical Mass Spectrometry Core, NIDDK, NIH, Bethesda, MD, USA.
Nat Commun. 2021 Jun 8;12(1):3418. doi: 10.1038/s41467-021-23745-1.
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.
抗真菌药物 5-氟胞嘧啶（5-FC）用于治疗多种真菌感染，但由于耐药性迅速发展，不适合单独使用。在这里，我们发现隐球菌在暴露于高于最小抑菌浓度数倍的浓度时，会以很高的频率对 5-FC 产生耐药性。耐药克隆的基因组中包含与 5-FC 耐药相关和不相关的基因改变，这表明 5-FC 在中等浓度下可能具有诱变作用。FCY2（编码已知的 5-FC 摄取通透酶）、FCY1、FUR1、UXS1（编码将 UDP-葡萄糖醛酸转化为 UDP-木糖的酶）和 URA6 中的突变有助于 5-FC 耐药。uxs1 突变体积累 UDP-葡萄糖醛酸，这似乎下调了通透酶 FCY2 的表达，并减少了药物的细胞摄取。UGD1（编码 UDP-葡萄糖醛酸合成所需的基因）或转录因子 NRG1 的其他突变抑制了 uxs1 突变体中 UDP-葡萄糖醛酸的积累和 5-FC 耐药性。
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