Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis
Su Zhang,
Xuefeng Zhou,
Min Ou,
Xiangdong Fu,
Qiao Lin,
Xiaoyu Tao,
Zhaoqin Wang,
Aimei Liu,
Guobao Li,
Yuzhong Xu,
Guoliang Zhang
Affiliations
Su Zhang
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
Xuefeng Zhou
Guangzhou Medical University , Guangzhou, China
Min Ou
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
Xiangdong Fu
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
Qiao Lin
Department of Clinical Laboratory, The Baoan People’s Hospital of Shenzhen, The Second Affiliated Hospital of Shenzhen University , Shenzhen, China
Xiaoyu Tao
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
Zhaoqin Wang
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
Aimei Liu
Department of Tuberculosis, Guangxi Chest Hospital , Liuzhou, China
Guobao Li
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
Yuzhong Xu
Department of Clinical Laboratory, The Baoan People’s Hospital of Shenzhen, The Second Affiliated Hospital of Shenzhen University , Shenzhen, China
Guoliang Zhang
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
ABSTRACT Drug-resistant tuberculosis (TB) poses a major threat to global TB control; consequently, there is an urgent need to develop novel anti-TB drugs or strategies. Host-directed therapy (HDT) is emerging as an effective treatment strategy, especially for drug-resistant TB. This study evaluated the effects of berbamine (BBM), a bisbenzylisoquinoline alkaloid, on mycobacterial growth in macrophages. BBM inhibited intracellular Mycobacterium tuberculosis (Mtb) growth by promoting autophagy and silencing ATG5, partially abolishing the inhibitory effect. In addition, BBM increased intracellular reactive oxygen species (ROS), while the antioxidant N-acetyl-L-cysteine (NAC) abolished BBM-induced autophagy and the ability to inhibit Mtb survival. Furthermore, the increased intracellular Ca2+ concentration induced by BBM was regulated by ROS, and BAPTA-AM, an intracellular Ca2+-chelating agent, could block ROS-mediated autophagy and Mtb clearance. Finally, BBM could inhibit the survival of drug-resistant Mtb. Collectively, these findings provide evidence that BBM, a Food and Drug Administration (FDA)–approved drug, could effectively clear drug-sensitive and -resistant Mtb through regulating ROS/Ca2+ axis-mediated autophagy and has potential as an HDT candidate for TB therapy. IMPORTANCE It is urgent to develop novel treatment strategies against drug-resistant TB, and HDT provides a promising approach to fight drug-resistant TB by repurposing old drugs. Our studies demonstrate, for the first time, that BBM, an FDA-approved drug, not only potently inhibits intracellular drug-sensitive Mtb growth but also restricts drug-resistant Mtb by promoting macrophage autophagy. Mechanistically, BBM activates macrophage autophagy by regulating the ROS/Ca2+ axis. In conclusion, BBM could be considered as an HDT candidate and may contribute to improving the outcomes or shortening the treatment course of drug-resistant TB.
