In Vitro Efficacy of Ebselen and BAY 11-7082 Against Naegleria fowleri.
In Vitro Efficacy of Ebselen and BAY 11-7082 Against Naegleria fowleri.
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DOI：
10.3389/fmicb.2018.00414
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发表时间：
2018
影响因子：
5.2
通讯作者：
McKerrow JH
中科院分区：
文献类型：
--
作者：
Debnath A;Nelson AT;Silva-Olivares A;Shibayama M;Siegel D;McKerrow JH
原发性阿米巴脑膜脑炎 (PAM) 是由自由生活的福氏阿米巴原虫（俗称“食脑阿米巴”）引起的致命感染。治疗 PAM 的首选药物是抗真菌两性霉素 B 和抗利什曼尼米替福辛，但这些药物并未获得 FDA 批准用于该适应症，并且两性霉素 B 的使用会带来严重的不良反应。此外，接受联合疗法治疗的患者很少能在 PAM 中存活下来。因此，开发有效的药物是避免未来儿童死亡的一个关键的未满足需求。由于福氏奈瑟菌会引起大脑广泛的炎症，因此选择可以进入大脑杀死阿米巴原虫的化合物非常重要。在这项研究中，我们鉴定了两种中枢神经系统 (CNS) 活性化合物，依布硒啉和 BAY 11-7082 具有杀阿米巴活性，EC50 分别为 6.2 和 1.6 μM。密切相关的 BAY 11-7085 也被发现对福氏奈瑟菌具有活性，其 EC50 与 BAY 11-7082 相似。我们合成了一种可溶性依布硒啉类似物，其具有与依布硒啉类似的杀阿米巴活性。用 EC50 浓度的依布硒啉孵育 48 小时的福氏奈瑟氏菌滋养体的透射电子显微镜显示，细胞质膜发生变化，核膜缺失，并出现电子致密颗粒。将福氏奈瑟菌滋养体与 EC50 浓度的 BAY 11-7082 和 BAY 11-7085 一起孵育 48 小时，结果显示细胞质中存在大脂滴、细胞质和核膜破裂以及出现多个囊泡和染色质残基。血脑屏障可渗透的杀阿米巴化合物具有作为耐格里阿米巴感染新药的潜力。
Primary amebic meningoencephalitis (PAM) is a fatal infection caused by the free-living ameba Naegleria fowleri, popularly known as the “brain-eating ameba.” The drugs of choice in treating PAM are the antifungal amphotericin B and an antileishmanial miltefosine, but these are not FDA-approved for this indication and use of amphotericin B is associated with severe adverse effects. Moreover, very few patients treated with the combination therapy have survived PAM. Therefore, development of efficient drugs is a critical unmet need to avert future deaths of children. Since N. fowleri causes extensive inflammation in the brain it is important to select compounds that can enter brain to kill ameba. In this study, we identified two central nervous system (CNS) active compounds, ebselen and BAY 11-7082 as amebicidal with EC50 of 6.2 and 1.6 μM, respectively. The closely related BAY 11-7085 was also found active against N. fowleri with EC50 similar to BAY 11-7082. We synthesized a soluble ebselen analog, which had amebicidal activity similar to ebselen. Transmission electron microscopy of N. fowleri trophozoites incubated for 48 h with EC50 concentration of ebselen showed alteration in the cytoplasmic membrane, loss of the nuclear membrane, and appearance of electron-dense granules. Incubation of N. fowleri trophozoites with EC50 concentrations of BAY 11-7082 and BAY 11-7085 for 48 h showed the presence of large lipid droplets in the cytoplasm, disruption of cytoplasmic and nuclear membranes and appearance of several vesicles and chromatin residues. Blood-brain barrier permeable amebicidal compounds have potential as new drug leads for Naegleria infection.
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影响因子：
2.1
作者：
ALDAPE, K;HUIZINGA, H;MCKERROW, J
通讯作者：
MCKERROW, J
影响因子：
4.9
作者：
Goswick, SM;Brenner, GM
通讯作者：
Brenner, GM
影响因子：
3.8
作者：
Debnath, Anjan;Calvet, Claudia M;Podust, Larissa M
通讯作者：
Podust, Larissa M
影响因子：
2
作者：
Gautam, Parshotam Lal;Sharma, Shruti;Bansal, Rajinder
通讯作者：
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影响因子：
33.9
作者：
Johnson, Richard O.;Cope, Jennifer R.;Beach, Michael J.
通讯作者：
Beach, Michael J.