Chemosensitisation of drug-resistant and drug-sensitive yeast cells to antifungals
Chemosensitisation of drug-resistant and drug-sensitive yeast cells to antifungals
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DOI：
10.1016/j.ijantimicag.2006.08.037
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发表时间：
2007-02-01
影响因子：
10.8
通讯作者：
Subik, Julius
中科院分区：
文献类型：
--
作者：
Cernicka, Jana;Kozovska, Zuzana;Subik, Julius
酵母菌的多药耐药是由于调控药物外排转运蛋白表达的转录因子发生功能获得性突变而导致其编码基因过表达所致。我们已经使用多药耐药酿酒酵母pdr 3 -9突变株筛选了用于耐药性调节剂的合成化合物库。其中一种化合物，7-氯四唑[5，1-c]苯并[1，2，4]三嗪（CTBT），显示出弱的抗真菌活性，并强烈抑制酵母细胞的生长，与亚抑制浓度的其他抗真菌药物具有不同的作用模式。在固体和液体培养基上生长的酵母属、克鲁维酵母属和假丝酵母属中证明了CTBT的生物活性。CTBT的化学增敏作用，表现为增加氟康唑的抗真菌活性，在缺失了编码主要多药耐药转录因子Yap 1 p、Pdr`p和Pdr 3 p以及药物外排泵Pdr 5 p和Snq 2 p的基因的酵母突变株中得到证实。酿酒酵母或它们在交替假丝酵母和光滑假丝酵母中的对应物，分别命名为Cdr 1 p和Mdr 1 p。重要的是，CTBT还增加了过度表达外排泵的多药耐药细胞对氟康唑的敏感性。在亚抑制浓度的CTBT存在下生长的酵母细胞表现出改变的甾醇组合物和罗丹明6 G的略微增强的积累，这表明质膜在致敏中起作用。CTBT的这种新的化学增敏作用可以克服酵母菌的多药耐药性，这可能有助于耐药真菌病原体引起的感染的联合治疗。(c)2006年Elsevier B. V.和国际化疗学会。All rights reserved.
Multidrug resistance in yeast results from overexpression of genes encoding drug efflux transporters owing to gain-of-function mutations in transcription factors regulating their expression. We have screened a library of synthetic compounds for modulators of drug resistance using the multidrug-resistant Saccharomyces cerevisiae pdr3-9 mutant strain. One of the compounds, 7-chlorotetrazolo[5,1-c]benzo[ 1,2,4]triazine (CTBT), displayed weak antifungal activity and strongly inhibited the growth of yeast cells in combination with subinhibitory concentrations of other antifungals with a different mode of action. Biological activity of CTBT was demonstrated in Saccharomyces, Kluyveromyces and Candida yeast species grown on solid and in liquid media. The chemosensitising effect of CTBT, manifested as increased antifungal activity of fluconazole, was demonstrated in yeast mutant strains with deleted genes encoding the major multidrug resistance transcription factors Yap1p, Pdr`p and Pdr3p as well as the drug efflux pumps Pdr5p and Snq2p, in S. cerevisiae or their counterparts in Candida altricans and Candida glabrata, named Cdr1p and Mdr1p, respectively. Importantly, CTBT also increased the sensitivity to fluconazole in multidrug-resistant cells overexpressing the efflux pumps. Yeast cells grown in the presence of subinhibitory concentrations of CTBT exhibited an altered sterol composition and a slightly enhanced accumulation of Rhodamine 6G, which suggests that the plasma membrane plays a role in sensitisation. This novel chemosensitisation by CTBT that can overcome multidrug resistance in yeast may prove useful in combined treatment of infections caused by drug-resistant fungal pathogens. (c) 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.