Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb), results in significant morbidity and mortality worldwide. Host-directed therapy (HDT), including conventional drugs, is a promising anti-TB strategy that shows synergistic antibacterial effects when combined with anti-TB drugs. Here, the mycobactericidal effect of three anti-diabetic drugs was examined. Of these, only Troglitazone (Trog) enhanced the antimycobacterial effect in vitro and in vivo. This was due to Trog-mediated autophagy activation. Moreover, a knock-down experiment revealed that Trog activated autophagy and exhibited antimycobacterial activity through the LKB1-AMPK signaling pathway. Molecular docking and co-immunoprecipitation experiments demonstrated that Trog promoted LKB1 phosphorylation and activation by targeting STRADA. Finally, we found that Trog inhibited the intracellular survival of clinical isoniazid (INH)-resistant Mtb, and the combination of Trog and INH showed additive antibacterial effects against Mtb H37Rv. Taken together, anti-diabetic Trog may be repurposed as an HDT candidate and combined with first-line anti-TB drugs.

中文翻译：

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曲格列酮通过 LKB1-AMPKα 信号传导通过巨噬降低细胞内结核分枝杆菌存活率


由结核分枝杆菌 （Mtb） 引起的结核病 （TB） 在世界范围内导致严重的发病率和死亡率。宿主导向疗法 （HDT），包括常规药物，是一种很有前途的抗结核策略，当与抗结核药物联合使用时显示出协同抗菌作用。在这里，检查了三种抗糖尿病药物的分枝杆菌作用。其中，只有曲格列酮 （Trog） 增强了体外和体内的抗分枝杆菌作用。这是由于 Trog 介导的自噬激活。此外，敲低实验显示 Trog 激活自噬并通过 LKB1-AMPK 信号通路表现出抗分枝杆菌活性。分子对接和免疫共沉淀实验表明，Trog 通过靶向 STRADA 促进 LKB1 磷酸化和激活。最后，我们发现 Trog 抑制了临床异烟肼 （INH） 耐药 Mtb 的细胞内存活，并且 Trog 和 INH 的组合显示出对 Mtb H37Rv 的附加抗菌作用。综上所述，抗糖尿病 Trog 可能重新用作 HDT 候选药物，并与一线抗结核药物联合使用。