Novel Cell-Killing Mechanisms of Hydroxyurea and the Implication toward Combination Therapy for the Treatment of Fungal Infections.
Novel Cell-Killing Mechanisms of Hydroxyurea and the Implication toward Combination Therapy for the Treatment of Fungal Infections.
复制标题
羟基脲的新型细胞杀伤机制及其对治疗真菌感染的联合疗法的意义。
DOI：
10.1128/aac.00734-17
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发表时间：
2017
影响因子：
4.9
通讯作者：
Xu,Yong-Jie
中科院分区：
文献类型：
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作者：
Singh,Amanpreet;Agarwal,Ameeta;Xu,Yong-Jie
我们之前已经报道了影响麦角固醇合成的anerg11突变和血红素合成途径中的ahem13突变显著地使裂殖酵母粟酒裂殖酵母对羟基脲（HU）敏感（1，2）。在这里，我们表明，治疗Erg11和血红素生物合成表型的两个突变的抑制剂在致敏野生型细胞HU。重要的是，HU与血红素生物合成抑制剂sampangine和几种Erg11抑制剂（抗真菌唑类）协同作用，导致细胞死亡。由于协同药物相互作用也观察到在酿酒酵母和机会致病真菌病原体白色念珠菌中，协同作用可能是真核生物中保守的。有趣的是，我们的S.粟酒裂殖酵母的研究还发现了桑潘金与C.白色念珠菌因此，HU、桑潘金和唑类化合物的组合可作为治疗真菌感染的新方法进一步研究。
We have previously reported that anerg11mutation affecting ergosterol synthesis and ahem13mutation in the heme synthesis pathway significantly sensitize the fission yeast Schizosaccharomyces pombe to hydroxyurea (HU) (1, 2). Here we show that treatment with inhibitors of Erg11 and heme biosynthesis phenocopies the two mutations in sensitizing wild-type cells to HU. Importantly, HU synergistically interacts with the heme biosynthesis inhibitor sampangine and several Erg11 inhibitors, the antifungal azoles, in causing cell lethality. Since the synergistic drug interactions are also observed in the phylogenetically divergent Saccharomyces cerevisiae and the opportunistic fungal pathogen Candida albicans, the synergism is likely conserved in eukaryotes. Interestingly, our genetic data for S. pombe has also led to the discovery of a robust synergism between sampangine and the azoles in C. albicans. Thus, combinations of HU, sampangine, and the azoles can be further studied as a new method for the treatment of fungal infections.