Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.
Wadsworth Center, New York State Department of Health, Albany, New York, USA.
Antimicrob Agents Chemother. 2017 Oct 24;61(11). doi: 10.1128/AAC.00734-17. Print 2017 Nov.
We have previously reported that an mutation affecting ergosterol synthesis and a mutation in the heme synthesis pathway significantly sensitize the fission yeast 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 and the opportunistic fungal pathogen , the synergism is likely conserved in eukaryotes. Interestingly, our genetic data for has also led to the discovery of a robust synergism between sampangine and the azoles in Thus, combinations of HU, sampangine, and the azoles can be further studied as a new method for the treatment of fungal infections.
我们之前曾报道，影响麦角固醇合成的 突变和血红素合成途径中的 突变显著增强了裂殖酵母对羟基脲（HU）的敏感性（1,2）。在这里，我们表明，抑制 Erg11 和血红素生物合成的抑制剂处理可模拟两种突变，使野生型细胞对 HU 敏感。重要的是，HU 与血红素生物合成抑制剂桑巴林和几种 Erg11 抑制剂（抗真菌唑类药物）协同作用导致细胞致死。由于协同药物相互作用也在系统发育上不同的 和机会性真菌病原体 中观察到，因此协同作用可能在真核生物中保守。有趣的是，我们针对 的遗传数据还导致了在 中发现了桑巴林和唑类药物之间的强大协同作用。因此，HU、桑巴林和唑类药物的组合可以进一步研究作为治疗真菌感染的新方法。
