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Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca(2+) axis
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 effec...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10470588/ https://www.ncbi.nlm.nih.gov/pubmed/37382506 http://dx.doi.org/10.1128/mbio.00272-23 |
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author | Zhang, Su Zhou, Xuefeng Ou, Min Fu, Xiangdong Lin, Qiao Tao, Xiaoyu Wang, Zhaoqin Liu, Aimei Li, Guobao Xu, Yuzhong Zhang, Guoliang |
author_facet | Zhang, Su Zhou, Xuefeng Ou, Min Fu, Xiangdong Lin, Qiao Tao, Xiaoyu Wang, Zhaoqin Liu, Aimei Li, Guobao Xu, Yuzhong Zhang, Guoliang |
author_sort | Zhang, Su |
collection | PubMed |
description | 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 Ca(2+) concentration induced by BBM was regulated by ROS, and BAPTA-AM, an intracellular Ca(2+)-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/Ca(2+) 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/Ca(2+) 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. |
format | Online Article Text |
id | pubmed-10470588 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-104705882023-09-01 Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca(2+) axis Zhang, Su Zhou, Xuefeng Ou, Min Fu, Xiangdong Lin, Qiao Tao, Xiaoyu Wang, Zhaoqin Liu, Aimei Li, Guobao Xu, Yuzhong Zhang, Guoliang mBio Research Article 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 Ca(2+) concentration induced by BBM was regulated by ROS, and BAPTA-AM, an intracellular Ca(2+)-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/Ca(2+) 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/Ca(2+) 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. American Society for Microbiology 2023-06-29 /pmc/articles/PMC10470588/ /pubmed/37382506 http://dx.doi.org/10.1128/mbio.00272-23 Text en Copyright © 2023 Zhang et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Zhang, Su Zhou, Xuefeng Ou, Min Fu, Xiangdong Lin, Qiao Tao, Xiaoyu Wang, Zhaoqin Liu, Aimei Li, Guobao Xu, Yuzhong Zhang, Guoliang Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca(2+) axis |
title | Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca(2+) axis |
title_full | Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca(2+) axis |
title_fullStr | Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca(2+) axis |
title_full_unstemmed | Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca(2+) axis |
title_short | Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca(2+) axis |
title_sort | berbamine promotes macrophage autophagy to clear mycobacterium tuberculosis by regulating the ros/ca(2+) axis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10470588/ https://www.ncbi.nlm.nih.gov/pubmed/37382506 http://dx.doi.org/10.1128/mbio.00272-23 |
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