Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis

Zhang, Su1; Zhou, Xuefeng2; Ou, Min1; Fu, Xiangdong1; Lin, Qiao3; Tao, Xiaoyu1; Wang, Zhaoqin1; Liu, Aimei4; Li, Guobao1; Xu, Yuzhong3; Zhang, Guoliang1

2023-06-01

10.1128/mbio.00272-23

MBIO   影响因子和分区

2150-7511

["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.","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. IMPORTANCEIt 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."]

Mycobacterium tuberculosis berbamine autophagy ROS calcium

SCI

英语

第一 ; 通讯

National Key Research and Development Plan[2021YFA1300902] ; National Natural Science Foundation of China["82170009","82100013"] ; Guangdong Scientific and Technological Foundation["2019B1515120041","2020B1111170014"] ; Guangxi Scientific and Technological Foundations[AA22096027] ; Shenzhen Scientific and Technological Foundations["KCXFZ20211020163545004","KCXFZ202002011007083","JCYJ20190809104205706","JCYJ20180228162321234"]

Microbiology

Microbiology

WOS:001023845600001

AMER SOC MICROBIOLOGY

Web of Science

1.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Natl Clin Res Ctr Infect Dis, Guangdong Prov Clin Res Ctr TB, Shenzhen, Peoples R China
2.Guangzhou Med Univ, Guangzhou, Peoples R China
3.Shenzhen Univ, Baoan Peoples Hosp Shenzhen, Affiliated Hosp 2, Dept Clin Lab, Shenzhen, Peoples R China
4.Guangxi Chest Hosp, Dept TB, Liuzhou, Peoples R China

Zhang, Su,Zhou, Xuefeng,Ou, Min,et al. Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis[J]. MBIO,2023,14(4).

Zhang, Su.,Zhou, Xuefeng.,Ou, Min.,Fu, Xiangdong.,Lin, Qiao.,...&Zhang, Guoliang.(2023).Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis.MBIO,14(4).

Zhang, Su,et al."Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis".MBIO 14.4(2023).