Flucytosine antagonism of azole activity versus Candida glabrata: role of transcription factor Pdr1 and multidrug transporter Cdr1.
Flucytosine antagonism of azole activity versus Candida glabrata: role of transcription factor Pdr1 and multidrug transporter Cdr1.
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氟胞嘧啶对唑类活性与光滑念珠菌的拮抗作用：转录因子 Pdr1 和多药转运蛋白 Cdr1 的作用。
DOI：
10.1128/aac.02394-12
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发表时间：
2013
影响因子：
4.9
通讯作者：
Katiyar,Santosh
中科院分区：
文献类型：
--
作者：
Steier,Zoë;Vermitsky,John-Paul;Toner,Geoffrey;Gygax,ScottE;Edlind,Thomas;Katiyar,Santosh
近年来，机会性酵母光滑念珠菌的感染急剧增加。酵母菌感染的抗真菌治疗通常使用唑类，如氟康唑（FLC），但C。glabrata经常对这些麦角甾醇生物合成抑制剂产生抗性。嘧啶类似物氟胞嘧啶（5-氟胞嘧啶[5 FC]）与C相比具有高度活性。glabrata，但现在很少在临床上使用，这是由于对耐药性的类似关注，以及与用于对抗耐药性的高剂量相关的毒性。唑-5FC联合治疗可能会解决这些问题;然而，以前的研究表明，5 FC可能拮抗唑活性与C。光滑的在这里，我们报告说，在亚抑制浓度的5 FC拮抗FLC的活性4- 16倍，与8个C。试验的光滑分离株。5 FC拮抗活性的其他唑类类似，但只有不相关的抗真菌药物组合的影响。由于C. glabrata的结果从转录因子Pdr 1依赖性上调的多药转运蛋白基因CDR 1，我们推断，5 FC拮抗作用可能类似介导。事实上，5 FC-FLC拮抗作用在pdr 1 Δ和cdr 1 Δ菌株中被消除。为了进一步支持这一假设，5 FC暴露诱导CDR 1表达6倍，这种上调是Pdr 1依赖性的。与唑类相反，5 FC不是Cdr 1底物，因此其对Pdr 1的激活是出乎意料的。然而，我们观察到，5 FC暴露容易诱导娇小的突变体，表现出Pdr 1-dependentCDR 1上调。因此，线粒体功能障碍导致Pdr 1激活可能是5 FC拮抗唑活性与C的基础。光滑的
Infections with the opportunistic yeast Candida glabrata have increased dramatically in recent years. Antifungal therapy of yeast infections commonly employs azoles, such as fluconazole (FLC), but C. glabrata frequently develops resistance to these inhibitors of ergosterol biosynthesis. The pyrimidine analog flucytosine (5-fluorocytosine [5FC]) is highly active versus C. glabrata but is now rarely used clinically due to similar concerns over resistance and, a related concern, the toxicity associated with high doses used to counter resistance. Azole-5FC combination therapy would potentially address these concerns; however, previous studies suggest that 5FC may antagonize azole activity versus C. glabrata. Here, we report that 5FC at subinhibitory concentrations antagonized the activity of FLC 4- to 16-fold versus 8 of 8 C. glabrata isolates tested. 5FC antagonized the activity of other azoles similarly but had only indifferent effects in combination with unrelated antifungals. Since azole resistance in C. glabrata results from transcription factor Pdr1-dependent upregulation of the multidrug transporter geneCDR1, we reasoned that 5FC antagonism might be similarly mediated. Indeed, 5FC-FLC antagonism was abrogated inpdr1Δ andcdr1Δ strains. In further support of this hypothesis, 5FC exposure inducedCDR1expression 6-fold, and this upregulation was Pdr1 dependent. In contrast to azoles, 5FC is not a Cdr1 substrate and so its activation of Pdr1 was unexpected. We observed, however, that 5FC exposure readily induced petite mutants, which exhibit Pdr1-dependentCDR1upregulation. Thus, mitochondrial dysfunction resulting in Pdr1 activation is the likely basis for 5FC antagonism of azole activity versus C. glabrata.
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氟化嘧啶诱导小酵母突变体涉及的分子事件
DOI：
10.1007/bf00701248
发表时间：
1976
期刊：
Molecular and General Genetics MGG
影响因子：
--
作者：
S. Oliver;D. Williamson
通讯作者：
D. Williamson
念珠菌病的临床实践指南：2009 年实际情况，美国传染病学会
DOI：
--
发表时间：
2009
期刊：
影响因子：
--
作者：
Peter G. Pappas;C. Kauffman;David R. Andes;Daniel K. Benjamin;Thierry Calandra;John E. Edwards;Scott G. Filler;John Fremont Fisher;Bart Jan Kullberg;Luis Ostrosky;Annette C. Reboli;John H. Rex;Thomas J. Walsh;Jack D. Sobel
通讯作者：
Jack D. Sobel
影响因子：
5.5
作者：
Alves, Izabel Almeida;Bandeira, Laissa Arevalo;Alves, Sydney Hartz
通讯作者：
Alves, Sydney Hartz
影响因子：
4.9
作者：
Gygax, Scott E.;Vermitsky, John-Paul;Trama, Jason P.
通讯作者：
Trama, Jason P.
影响因子：
4.9
作者：
Barchiesi, F;Spreghini, E;Scalise, G
通讯作者：
Scalise, G