Bi Jing, Guo Qinglong, Gong Yaqi, Chen Xi, Wu Haojia, Song Li, Xu Yating, Ou Min, Wang Zhaoqin, Chen Jiean, Jiang Chenran, Liu Aimei, Li Guobao, Zhang Guoliang
National Clinical Research Center for Infectious Diseases, Guangdong Provincial Clinical Research Center for Tuberculosis, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China.
Shenzhen Bay Laboratory, Pingshan Translational Medicine Center, Shenzhen, China.
J Infect Dis. 2025 Mar 17;231(3):e553-e565. doi: 10.1093/infdis/jiae523.
Tuberculosis caused by Mycobacterium tuberculosis (Mtb), results in significant disease and death worldwide. Host-directed therapy, including conventional drugs, is a promising antituberculosis strategy that shows synergistic antibacterial effects when combined with antituberculosis drugs. Here, the mycobactericidal effect of 3 antidiabetic 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 serine/threonine-protein kinase STK11 (LKB1)-5'-AMP-activated protein kinase (AMPK) signaling pathway. Molecular docking and coimmunoprecipitation experiments demonstrated that Trog promoted LKB1 phosphorylation and activation by targeting STE20-related kinase adapter protein alpha (STRADA). Finally, we found that Trog inhibited the intracellular survival of clinical isoniazid-resistant Mtb, and the combination of Trog and isoniazid showed additive antibacterial effects against Mtb H37Rv. Taken together, antidiabetic Trog may be repurposed as a candidate for host-directed therapy and combined with first-line antituberculosis drugs.
由结核分枝杆菌（Mtb）引起的结核病在全球范围内导致了严重的疾病和死亡。宿主导向疗法，包括传统药物，是一种有前景的抗结核策略，与抗结核药物联合使用时显示出协同抗菌作用。在此，研究了3种抗糖尿病药物的杀菌作用。其中，只有曲格列酮（Trog）在体外和体内增强了抗分枝杆菌作用。这是由于Trog介导的自噬激活。此外，一项敲低实验表明，Trog通过丝氨酸/苏氨酸蛋白激酶STK11（LKB1）-5'-AMP激活蛋白激酶（AMPK）信号通路激活自噬并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STE20相关激酶衔接蛋白α（STRADA）促进LKB1磷酸化和激活。最后，我们发现Trog抑制临床异烟肼耐药Mtb的细胞内存活，并且Trog与异烟肼联合使用对Mtb H37Rv显示出相加抗菌作用。综上所述，抗糖尿病药物Trog可能被重新用作宿主导向疗法的候选药物，并与一线抗结核药物联合使用。
