The free-living amebae Naegleria, Acanthamoeba, and Balamuthia cause rare but life-threatening infections. All three parasites can cause meningoencephalitis. Acanthamoeba can also cause chronic keratitis and both Balamuthia and Acanthamoeba can cause skin and systemic infections. There are minimal drug development pipelines for these pathogens despite a lack of available treatment regimens and high fatality rates. To identify anti-amebic drugs, we screened 159 compounds from a high-value repurposed library against trophozoites of the three amebae. Our efforts identified 38 compounds with activity against at least one ameba. Multiple drugs that bind the ATP-binding pocket of mTOR and PI3K are active, highlighting these compounds as important inhibitors of these parasites. Importantly, 24 active compounds have progressed at least to phase II clinical studies and overall 15 compounds were active against all three amebae. Based on central nervous system (CNS) penetration or exceptional potency against one amebic species, we identified sixteen priority compounds for the treatment of meningoencephalitis caused by these pathogens. The top five compounds are (i) plicamycin, active against all three free-living amebae and previously U.S. Food and Drug Administration (FDA) approved, (ii) TG02, active against all three amebae, (iii and iv) FDA-approved panobinostat and FDA orphan drug lestaurtinib, both highly potent against Naegleria, and (v) GDC-0084, a CNS penetrant mTOR inhibitor, active against at least two of the three amebae. These results set the stage for further investigation of these clinically advanced compounds for treatment of infections caused by the free-living amebae, including treatment of the highly fatal meningoencephalitis.

中文翻译：

---

鉴定普卡霉素、TG02、帕比司他、lestaurtinib 和 GDC-0084 作为治疗由自由生活的阿米巴原虫、棘阿米巴和 Balamuthia 引起的中枢神经系统感染的有前途的化合物。

自由生活的阿米巴原虫、耐格里阿米巴原虫、棘阿米巴原虫和巴拉穆斯原虫会引起罕见但危及生命的感染。所有三种寄生虫均可引起脑膜脑炎。棘阿米巴还可引起慢性角膜炎，巴拉穆斯菌和棘阿米巴均可引起皮肤和全身感染。尽管缺乏可用的治疗方案且死亡率很高，但针对这些病原体的药物开发渠道却很少。为了鉴定抗阿米巴药物，我们从高价值的改造库中筛选了 159 种针对三种阿米巴滋养体的化合物。我们的努力鉴定出 38 种化合物对至少一种阿米巴原虫具有活性。多种与 mTOR 和 PI3K 的 ATP 结合袋结合的药物具有活性，突出显示这些化合物是这些寄生虫的重要抑制剂。重要的是，24 种活性化合物至少已进入 II 期临床研究，总共 15 种化合物对所有三种阿米巴都有活性。基于中枢神经系统 (CNS) 渗透性或针对一种阿米巴物种的特殊功效，我们确定了 16 种优先化合物用于治疗由这些病原体引起的脑膜脑炎。排名前五的化合物是 (i) 普卡霉素，对所有三种自由生活的阿米巴有活性，并且之前已获得美国食品和药物管理局 (FDA) 批准；(ii) TG02，对所有三种阿米巴有活性；(iii 和 iv) FDA 批准的帕比司他(v) GDC-0084，一种中枢神经系统渗透性 mTOR 抑制剂，对三种阿米巴中的至少两种具有活性。这些结果为进一步研究这些临床先进化合物治疗自由生活的阿米巴引起的感染奠定了基础，包括治疗高度致命的脑膜脑炎。