Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis
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...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-08-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00272-23 |
| _version_ | 1797730237079879680 |
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| author | Su Zhang Xuefeng Zhou Min Ou Xiangdong Fu Qiao Lin Xiaoyu Tao Zhaoqin Wang Aimei Liu Guobao Li Yuzhong Xu Guoliang Zhang |
| author_facet | Su Zhang Xuefeng Zhou Min Ou Xiangdong Fu Qiao Lin Xiaoyu Tao Zhaoqin Wang Aimei Liu Guobao Li Yuzhong Xu Guoliang Zhang |
| author_sort | Su Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T11:41:21Z |
| format | Article |
| id | doaj.art-292b5bc0df694691aa0f1c8e8993ca4f |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-03-12T11:41:21Z |
| publishDate | 2023-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-292b5bc0df694691aa0f1c8e8993ca4f2023-08-31T15:04:20ZengAmerican Society for MicrobiologymBio2150-75112023-08-0114410.1128/mbio.00272-23Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axisSu Zhang0Xuefeng Zhou1Min Ou2Xiangdong Fu3Qiao Lin4Xiaoyu Tao5Zhaoqin Wang6Aimei Liu7Guobao Li8Yuzhong Xu9Guoliang Zhang10National 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, ChinaGuangzhou Medical University , Guangzhou, ChinaNational 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, ChinaNational 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, ChinaDepartment of Clinical Laboratory, The Baoan People’s Hospital of Shenzhen, The Second Affiliated Hospital of Shenzhen University , Shenzhen, ChinaNational 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, ChinaNational 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, ChinaDepartment of Tuberculosis, Guangxi Chest Hospital , Liuzhou, ChinaNational 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, ChinaDepartment of Clinical Laboratory, The Baoan People’s Hospital of Shenzhen, The Second Affiliated Hospital of Shenzhen University , Shenzhen, ChinaNational 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, ChinaABSTRACT 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.https://journals.asm.org/doi/10.1128/mbio.00272-23Mycobacterium tuberculosisberbamineautophagyROScalcium |
| spellingShingle | Su Zhang Xuefeng Zhou Min Ou Xiangdong Fu Qiao Lin Xiaoyu Tao Zhaoqin Wang Aimei Liu Guobao Li Yuzhong Xu Guoliang Zhang Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis mBio Mycobacterium tuberculosis berbamine autophagy ROS calcium |
| title | Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis |
| title_full | Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis |
| title_fullStr | Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis |
| title_full_unstemmed | Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis |
| title_short | Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca2+ axis |
| title_sort | berbamine promotes macrophage autophagy to clear mycobacterium tuberculosis by regulating the ros ca2 axis |
| topic | Mycobacterium tuberculosis berbamine autophagy ROS calcium |
| url | https://journals.asm.org/doi/10.1128/mbio.00272-23 |
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