Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093-0756, United States.
ACS Chem Neurosci. 2020 Aug 19;11(16):2464-2471. doi: 10.1021/acschemneuro.0c00165. Epub 2020 May 26.
Primary amebic meningoencephalitis, caused by brain infection with a free-living ameba, , 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 encodes genes for both selenocysteine biosynthesis and thioredoxin reductases, we tested the effect of auranofin against strains of different genotypes from the USA, Europe, and Australia. Auranofin was equipotent against all tested strains with an EC 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 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.
原发性阿米巴脑膜脑炎是由自由生活的阿米巴引起的脑部感染导致的，会导致大脑广泛炎症，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 联合其他药物，但两性霉素 B 的使用会引起严重的不良反应。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、起效迅速的药物仍然是避免未来死亡的迫切需求。由于美国食品和药物管理局 (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和硫氧还蛋白还原酶抑制剂，而 的基因组编码了硒代半胱氨酸生物合成和硫氧还蛋白还原酶的基因，因此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 菌株的影响。金诺芬对所有测试菌株的疗效相当，EC 为 1-2 μM。我们在不同时间点的生长抑制研究表明，金诺芬起效迅速，在药物暴露 16 小时内即可达到约 90%的生长抑制。短暂暴露于金诺芬会导致细胞内活性氧物质的积累。这与金诺芬抑制抗氧化途径的作用一致。此外，金诺芬与两性霉素 B 的联合使用可使 95%的生长受到抑制，两性霉素 B 的剂量减少 2-9 倍，金诺芬的剂量减少 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。
