Bazedoxifene Suppresses Intracellular <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Growth by Enhancing Autophagy

ABSTRACT 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 in...

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Autores principales:	Qi Ouyang, Kehong Zhang, Dachuan Lin, Carl G. Feng, Yi Cai, Xinchun Chen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Mycobacterium tuberculosis autophagy bazedoxifene host-directed therapy Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/fa8b105207e2463ca1b5d1966b8e0618
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spelling	oai:doaj.org-article:fa8b105207e2463ca1b5d1966b8e06182021-11-15T15:29:17ZBazedoxifene Suppresses Intracellular <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Growth by Enhancing Autophagy10.1128/mSphere.00124-202379-5042https://doaj.org/article/fa8b105207e2463ca1b5d1966b8e06182020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00124-20https://doaj.org/toc/2379-5042ABSTRACT 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. IMPORTANCE 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.Qi OuyangKehong ZhangDachuan LinCarl G. FengYi CaiXinchun ChenAmerican Society for MicrobiologyarticleMycobacterium tuberculosisautophagybazedoxifenehost-directed therapyMicrobiologyQR1-502ENmSphere, Vol 5, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis autophagy bazedoxifene host-directed therapy Microbiology QR1-502
spellingShingle	Mycobacterium tuberculosis autophagy bazedoxifene host-directed therapy Microbiology QR1-502 Qi Ouyang Kehong Zhang Dachuan Lin Carl G. Feng Yi Cai Xinchun Chen Bazedoxifene Suppresses Intracellular <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Growth by Enhancing Autophagy
description	ABSTRACT 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. IMPORTANCE 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.
format	article
author	Qi Ouyang Kehong Zhang Dachuan Lin Carl G. Feng Yi Cai Xinchun Chen
author_facet	Qi Ouyang Kehong Zhang Dachuan Lin Carl G. Feng Yi Cai Xinchun Chen
author_sort	Qi Ouyang
title	Bazedoxifene Suppresses Intracellular <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Growth by Enhancing Autophagy
title_short	Bazedoxifene Suppresses Intracellular <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Growth by Enhancing Autophagy
title_full	Bazedoxifene Suppresses Intracellular <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Growth by Enhancing Autophagy
title_fullStr	Bazedoxifene Suppresses Intracellular <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Growth by Enhancing Autophagy
title_full_unstemmed	Bazedoxifene Suppresses Intracellular <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Growth by Enhancing Autophagy
title_sort	bazedoxifene suppresses intracellular <named-content content-type="genus-species">mycobacterium tuberculosis</named-content> growth by enhancing autophagy
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/fa8b105207e2463ca1b5d1966b8e0618
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Bazedoxifene Suppresses Intracellular <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Growth by Enhancing Autophagy

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