Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy
Since current strategies for the treatment of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have low efficacy and highly negative side effects, research on new treatments including novel drugs is essential for curing drug-resistant tuberculosis. Host-...
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doaj-00fb60ed563b434083aa2c13b8539d4b2020-11-25T03:16:37ZengAmerican Society for MicrobiologymSphere2379-50422020-04-0152e00124-2010.1128/mSphere.00124-20Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing AutophagyQi OuyangKehong ZhangDachuan LinCarl G. FengYi CaiXinchun ChenSince current strategies for the treatment of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have low efficacy and highly negative side effects, research on new treatments including novel drugs is essential for curing drug-resistant tuberculosis. Host-directed therapy (HDT) has become a promising idea to modulate host cell responses to enhance protective immunity against pathogens. Bazedoxifene (BZA), which belongs to a new generation of SERMs, shows the ability to inhibit the growth of M. tuberculosis in macrophages and is associated with autophagy. Our findings reveal a previously unrecognized antibacterial function of BZA. We propose that the mechanism of SERMs action in macrophages may provide a new potential measure for host-directed therapies against TB.Tuberculosis (TB) is still the leading killer caused by Mycobacterium tuberculosis infection. There is a clear need for new treatment strategy against TB. It has been reported that tamoxifen, known as a selective estrogen receptor modulator (SERM), exhibits antimycobacterial activity and inhibits M. tuberculosis growth in macrophages. However, it remains unknown whether such antimicrobial activity is a general property of all SERMs and how it works. In this study, we identified that bazedoxifene (BZA), a newer SERM, inhibits intracellular M. tuberculosis growth in macrophages. BZA treatment increases autophagosome formation and LC3B-II protein expression in M. tuberculosis-infected macrophages. We further demonstrated that the enhancement of autophagy by BZA is dependent on increased reactive oxygen species (ROS) production and associated with phosphorylation of Akt/mTOR signaling. In summary, our data reveal a previously unappreciated antimicrobial function of BZA and suggest that future investigation focusing on the mechanism of action of SERMs in macrophages may lead to new host-directed therapies against TB.https://doi.org/10.1128/mSphere.00124-20mycobacterium tuberculosisautophagybazedoxifenehost-directed therapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Qi Ouyang Kehong Zhang Dachuan Lin Carl G. Feng Yi Cai Xinchun Chen |
spellingShingle |
Qi Ouyang Kehong Zhang Dachuan Lin Carl G. Feng Yi Cai Xinchun Chen Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy mSphere mycobacterium tuberculosis autophagy bazedoxifene host-directed therapy |
author_facet |
Qi Ouyang Kehong Zhang Dachuan Lin Carl G. Feng Yi Cai Xinchun Chen |
author_sort |
Qi Ouyang |
title |
Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy |
title_short |
Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy |
title_full |
Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy |
title_fullStr |
Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy |
title_full_unstemmed |
Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy |
title_sort |
bazedoxifene suppresses intracellular mycobacterium tuberculosis growth by enhancing autophagy |
publisher |
American Society for Microbiology |
series |
mSphere |
issn |
2379-5042 |
publishDate |
2020-04-01 |
description |
Since current strategies for the treatment of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have low efficacy and highly negative side effects, research on new treatments including novel drugs is essential for curing drug-resistant tuberculosis. Host-directed therapy (HDT) has become a promising idea to modulate host cell responses to enhance protective immunity against pathogens. Bazedoxifene (BZA), which belongs to a new generation of SERMs, shows the ability to inhibit the growth of M. tuberculosis in macrophages and is associated with autophagy. Our findings reveal a previously unrecognized antibacterial function of BZA. We propose that the mechanism of SERMs action in macrophages may provide a new potential measure for host-directed therapies against TB.Tuberculosis (TB) is still the leading killer caused by Mycobacterium tuberculosis infection. There is a clear need for new treatment strategy against TB. It has been reported that tamoxifen, known as a selective estrogen receptor modulator (SERM), exhibits antimycobacterial activity and inhibits M. tuberculosis growth in macrophages. However, it remains unknown whether such antimicrobial activity is a general property of all SERMs and how it works. In this study, we identified that bazedoxifene (BZA), a newer SERM, inhibits intracellular M. tuberculosis growth in macrophages. BZA treatment increases autophagosome formation and LC3B-II protein expression in M. tuberculosis-infected macrophages. We further demonstrated that the enhancement of autophagy by BZA is dependent on increased reactive oxygen species (ROS) production and associated with phosphorylation of Akt/mTOR signaling. In summary, our data reveal a previously unappreciated antimicrobial function of BZA and suggest that future investigation focusing on the mechanism of action of SERMs in macrophages may lead to new host-directed therapies against TB. |
topic |
mycobacterium tuberculosis autophagy bazedoxifene host-directed therapy |
url |
https://doi.org/10.1128/mSphere.00124-20 |
work_keys_str_mv |
AT qiouyang bazedoxifenesuppressesintracellularmycobacteriumtuberculosisgrowthbyenhancingautophagy AT kehongzhang bazedoxifenesuppressesintracellularmycobacteriumtuberculosisgrowthbyenhancingautophagy AT dachuanlin bazedoxifenesuppressesintracellularmycobacteriumtuberculosisgrowthbyenhancingautophagy AT carlgfeng bazedoxifenesuppressesintracellularmycobacteriumtuberculosisgrowthbyenhancingautophagy AT yicai bazedoxifenesuppressesintracellularmycobacteriumtuberculosisgrowthbyenhancingautophagy AT xinchunchen bazedoxifenesuppressesintracellularmycobacteriumtuberculosisgrowthbyenhancingautophagy |
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1715261377126334464 |