Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway.
Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway.
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DOI：
10.3389/fcimb.2017.00004
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发表时间：
2017
影响因子：
5.7
通讯作者：
Seleem MN
中科院分区：
文献类型：
--
作者：
Thangamani S;Maland M;Mohammad H;Pascuzzi PE;Avramova L;Koehler CM;Hazbun TR;Seleem MN
目前的抗真菌疗法在治疗侵袭性真菌感染方面效果有限。此外，新型抗真菌药物的开发目前无法跟上对安全有效新药的迫切需求。金诺芬是 FDA 批准用于治疗类风湿性关节炎的药物，可抑制多种临床分离真菌的生长，是一种具有先前未开发的作用机制的新型抗真菌药物。除了金诺芬对浮游真菌具有有效的抗真菌活性外，该药物还可显着降低生物膜中包裹的念珠菌细胞的代谢活性。使用杂合酿酒酵母缺失菌株进行无偏化学基因组分析，结合生长测定，揭示了金诺芬抗真菌活性的三个可能靶点：mia40、acn9 和 coa4。 Mia40 因其在导入线粒体的富含半胱氨酸的蛋白质的氧化中发挥重要作用而受到特别关注。生化分析证实金诺芬靶向 Mia40-Erv1 通路，因为该药物以类似于对照 MB-7 的剂量依赖性方式抑制 Mia40 与其底物 Cmc1 相互作用。此外，与野生型酵母相比，过表达 Erv1 的酵母线粒体表现出对金诺芬的抗性，因为观察到 Cmc1 导入量增加。在新型隐球菌感染的秀丽隐杆线虫动物模型中进一步检查了金诺芬的体内抗真菌活性。金诺芬显着降低了受感染的秀丽隐杆线虫中的真菌负荷。总的来说，本研究提供了有价值的证据，表明金诺芬有望被重新用作一种新型抗真菌药物，并可能为当前治疗真菌感染的方法提供安全、有效和快速的补充。
Current antifungal therapies have limited effectiveness in treating invasive fungal infections. Furthermore, the development of new antifungal is currently unable to keep pace with the urgent demand for safe and effective new drugs. Auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, inhibits growth of a diverse array of clinical isolates of fungi and represents a new antifungal agent with a previously unexploited mechanism of action. In addition to auranofin's potent antifungal activity against planktonic fungi, this drug significantly reduces the metabolic activity of Candida cells encased in a biofilm. Unbiased chemogenomic profiling, using heterozygous S. cerevisiae deletion strains, combined with growth assays revealed three probable targets for auranofin's antifungal activity—mia40, acn9, and coa4. Mia40 is of particular interest given its essential role in oxidation of cysteine rich proteins imported into the mitochondria. Biochemical analysis confirmed auranofin targets the Mia40-Erv1 pathway as the drug inhibited Mia40 from interacting with its substrate, Cmc1, in a dose-dependent manner similar to the control, MB-7. Furthermore, yeast mitochondria overexpressing Erv1 were shown to exhibit resistance to auranofin as an increase in Cmc1 import was observed compared to wild-type yeast. Further in vivo antifungal activity of auranofin was examined in a Caenorhabditis elegans animal model of Cryptococcus neoformans infection. Auranofin significantly reduced the fungal load in infected C. elegans. Collectively, the present study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antifungal agent and may offer a safe, effective, and quick supplement to current approaches for treating fungal infections.