The pathogen Mycobacterium 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.

病原体结核分枝杆菌(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治疗结核病 (TB) 的宿主导向疗法 (HDT) 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 Mtb 的存活。酵母化学遗传学方法将 Pik1 鉴定为 clionamines 的靶蛋白。生物素化的可丽耐胺 B 从酵母细胞裂解物中拉下 Pik1，可丽耐胺类似物抑制酵母高尔基体膜中 4-磷酸磷脂 (PI4P) 的产生。Clionamine 和阳离子两亲药物 (CAD) 的化学遗传谱密切相关，将 Clionamine 的作用模式与 PI4P 在囊泡室中的共定位联系起来。