Clionamines stimulate autophagy, inhibit Mycobacterium tuberculosis survival in macrophages, and target Pik1
Clionamines stimulate autophagy, inhibit Mycobacterium tuberculosis survival in macrophages, and target Pik1
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Clionamines 刺激自噬，抑制巨噬细胞中结核分枝杆菌的存活，并靶向 Pik1
DOI：
10.1016/j.chembiol.2021.07.017
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发表时间：
2021
影响因子：
8.6
通讯作者：
RJ.
中科院分区：
文献类型：
--
作者：
Persaud;R.;Li;SC.;Chao;JD.;Forestieri;R.;Donohue;E.;Balgi;AD.;Zheng;X.;Chao;JT.;Yashiroda;Y.;Yoshimura;M.;Loewen;CJR.;Gingras;AC.;Boone;C.;Av-Gay;Y.;Roberge;M.;Andersen;RJ.
结核分枝杆菌（Mycobacterium tuberculosis，Mtb）通过干扰巨噬细胞中的自噬和吞噬体成熟来逃避先天免疫系统，因此，自噬的小分子刺激代表了用于治疗结核病（TB）的宿主导向治疗（host-directed therapeutic，HDTs）方法。在这里，我们展示了海洋天然产物clionamines激活自噬并抑制巨噬细胞中的Mtb存活。酵母化学遗传学方法将Pik 1鉴定为氯胺的靶蛋白。生物素化的氯离子胺B从酵母细胞裂解物中拉下Pik 1，而氯离子胺类似物则抑制酵母高尔基体膜中磷脂酰4-磷酸（PI 4 P）的产生。氯硝柳胺和阳离子两亲性药物（CAD）的化学遗传学特征密切相关，将氯硝柳胺的作用模式与泡状隔室中的PI 4P共定位联系起来。小干扰RNA（siRNA）敲低PI 4KB（Pik 1的人类同源物）抑制Mtb在巨噬细胞中的存活，鉴定PI 4KB为开发用于治疗TB的HDT药物的努力的未开发的分子靶标。
The pathogenMycobacterium tuberculosis(Mtb) evades the innate immune system by interfering with autophagy and phagosomal maturation in macrophages, and, as a result, small molecule stimulation of autophagy represents a host-directed therapeutics (HDTs) approach for treatment of tuberculosis (TB). Here we show the marine natural product clionamines activate autophagy and inhibit Mtb survival in macrophages. A yeast chemical-genetics approach identified Pik1 as target protein of the clionamines. Biotinylated clionamine B pulled down Pik1 from yeast cell lysates and a clionamine analog inhibited phosphatidyl 4-phosphate (PI4P) production in yeast Golgi membranes. Chemical-genetic profiles of clionamines and cationic amphiphilic drugs (CADs) are closely related, linking the clionamine mode of action to co-localization with PI4P in a vesicular compartment. Small interfering RNA (siRNA) knockdown of PI4KB, a human homolog of Pik1, inhibited the survival of Mtb in macrophages, identifying PI4KB as an unexploited molecular target for efforts to develop HDT drugs for treatment of TB.