Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy

  • mSphere. 2020 Apr 8;5(2):e00124-20. doi: 10.1128/mSphere.00124-20.
Qi Ouyang  1 ,  Kehong Zhang  1  2 ,  Dachuan Lin  1 ,  Carl G Feng  1  3 ,  Yi Cai  4 ,  Xinchun Chen  4
Affiliations
  • 1. Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, School of Medicine, Shenzhen University, Shenzhen, China.
  • 2. Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany.
  • 3. Immunology and Host Defense Group, Department of Infectious Diseases and Immunology, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
  • 4. Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, School of Medicine, Shenzhen University, Shenzhen, China [email protected] [email protected].
PMID: 32269154 DOI: 10.1128/mSphere.00124-20
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.

Keywords
Mycobacterium tuberculosis; autophagy; bazedoxifene; host-directed therapy.
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