Activity of Auranofin against Multiple Genotypes of Naegleria fowleri and Its Synergistic Effect with Amphotericin B In Vitro.,ACS Chemical Neuroscience

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Activity of Auranofin against Multiple Genotypes of Naegleria fowleri and Its Synergistic Effect with Amphotericin B In Vitro.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-05-11 , DOI: 10.1021/acschemneuro.0c00165
Jose Ignacio Escrig ₁ , Hye Jee Hahn ₁ , Anjan Debnath ₁

Affiliation

Primary amebic meningoencephalitis, caused by brain infection with a free-living ameba, Naegleria fowleri, leads to extensive inflammation of the brain and death within 3–7 days after symptoms begin. Treatment of primary amebic meningoencephalitis relies on amphotericin B in combination with other drugs, but use of amphotericin B is associated with severe adverse effects. Despite a fatality rate of over 97%, economic incentive to invest in development of antiamebic drugs by the pharmaceutical industry is lacking. Development of safe and rapidly acting drugs remains a critical unmet need to avert future deaths. Since FDA-approved anti-inflammatory and antiarthritic drug auranofin is a known inhibitor of selenoprotein synthesis and thioredoxin reductase and the genome of N. fowleri encodes genes for both selenocysteine biosynthesis and thioredoxin reductases, we tested the effect of auranofin against N. fowleri strains of different genotypes from the USA, Europe, and Australia. Auranofin was equipotent against all tested strains with an EC₅₀ of 1–2 μM. Our growth inhibition study at different time points demonstrated that auranofin is fast-acting, and ∼90% growth inhibition was achieved within 16 h of drug exposure. A short exposure of N. fowleri to auranofin led to the accumulation of intracellular reactive oxygen species. This is consistent with auranofin’s role in inhibiting antioxidant pathways. Further, combination of auranofin and amphotericin B led to 95% of growth inhibition with 2–9-fold dose reduction for amphotericin B and 3–20-fold dose reduction for auranofin. Auranofin has the potential to be repurposed for the treatment of primary amebic meningoencephalitis.

中文翻译：

金诺芬对福氏耐格里菌多种基因型的活性及其与两性霉素 B 的体外协同作用。

原发性阿米巴脑膜脑炎是由自由生活的阿米巴原虫 ( Naegleria fowleri)脑部感染引起的，可导致脑部广泛炎症并在症状出现后 3-7 天内死亡。原发性阿米巴脑膜脑炎的治疗依赖于两性霉素 B 与其他药物联合使用，但使用两性霉素 B 会出现严重的不良反应。尽管死亡率超过 97%，但制药行业缺乏投资开发抗阿米巴药物的经济动力。开发安全和快速起效的药物仍然是避免未来死亡的关键未满足需求。由于 FDA 批准的抗炎和抗关节炎药物金诺芬是一种已知的硒蛋白合成抑制剂和硫氧还蛋白还原酶抑制剂，以及福氏猪笼草的基因组编码硒代半胱氨酸生物合成和硫氧还蛋白还原酶的基因，我们测试了金诺芬对来自美国、欧洲和澳大利亚的不同基因型的N. fowleri菌株的影响。Auranofin 对所有测试菌株均具有同等效力，EC ₅₀为 1–2 μM。我们在不同时间点的生长抑制研究表明，金诺芬是快速起效的，在药物暴露 16 小时内实现了约 90% 的生长抑制。N. fowleri 的短暂暴露金诺芬导致细胞内活性氧的积累。这与金诺芬在抑制抗氧化途径中的作用一致。此外，金诺芬和两性霉素 B 的组合导致 95% 的生长抑制，两性霉素 B 的剂量减少了 2-9 倍，金诺芬的剂量减少了 3-20 倍。金诺芬有可能被重新用于治疗原发性阿米巴脑膜脑炎。

更新日期：2020-05-11

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