Troglitazone reduces intracellular Mycobacterium tuberculosis survival via macrophage autophagy through LKB1-AMPKα signaling

• Published in: The Journal of infectious diseases 2024-10
• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiae523

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.