Flucytosine resistance in Cryptococcus gattii is indirectly mediated by the FCY2-FCY1-FUR1 pathway.
Flucytosine resistance in Cryptococcus gattii is indirectly mediated by the FCY2-FCY1-FUR1 pathway.
复制标题
格特隐球菌中的氟胞嘧啶抗性是由 FCY2-FCY1-FUR1 途径间接介导的。
DOI：
10.1093/mmy/myx135
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发表时间：
2018
期刊：
影响因子：
2.9
通讯作者：
Gelli,Angie
中科院分区：
文献类型：
--
作者：
Vu,Kiem;Thompson3rd,GeorgeR;Roe,ChandlerC;Sykes,JaneE;Dreibe,ElizabethM;Lockhart,ShawnR;Meyer,Wieland;Engelthaler,DavidM;Gelli,Angie
Cryptococcosis is an opportunistic fungal infection caused by members of the two sibling species complexes:Cryptococcus neoformansandCryptococcus gattii.Flucytosine (5FC) is one of the most widely used antifungals againstCryptococcusspp., yet very few studies have looked at the molecular mechanisms responsible for 5FC resistance in this pathogen. In this study, we examined 11C. gattiiclinical isolates of the major molecular type VGIII based on differential 5FC susceptibility and asked whether there were genomic changes in the key genes involved in flucytosine metabolism. Susceptibility assays and sequencing analysis revealed an association between a point mutation in the cytosine deaminase gene (FCY1) and 5FC resistance in two of the studied 5FC resistantC. gattiiVGIII clinical isolates, B9322 and JS5. This mutation results in the replacement of arginine for histidine at position 29 and occurs within a variable stretch of amino acids. Heterologous expression ofFCY1and spot sensitivity assays, however, demonstrated that this point mutation did not have any effect onFCY1activities and was not responsible for 5FC resistance. Comparative sequence analysis further showed that no changes in the amino acid sequence and no genomic alterations were observed within 1 kb of the upstream and downstream sequences of either cytosine permeases (FCY2-4) or uracil phosphoribosyltransferase (FUR1) genes in 5FC resistant and 5FC susceptibleC. gattiiVGIII isolates. The herein obtained results suggest that the observed 5FC resistance in the isolates B9322 and JS5 is due to changes in unknown protein(s) or pathway(s) that regulate flucytosine metabolism.
