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.
Highlights
Tuberculosis (TB) is still the leading killer caused by Mycobacterium tuberculosis infection
We investigated whether BZA could inhibit M. tuberculosis growth indirectly through enhancing macrophage bactericidal activity
We found that BZA treatment significantly increased autophagy in macrophages, regardless of M. tuberculosis infection, as evident from a significantly increased conversion of soluble LC3B-I to lipid bound LC3B-II (Fig. 2A and Fig. S2A)
Summary
Tuberculosis (TB) is still the leading killer caused by Mycobacterium tuberculosis infection. The emergence of drug-resistant TB [4], as in the case of multiple-drug-resistant TB (MDRTB) and extensively drug-resistant TB (XDR-TB) [5], has further impeded the effectiveness of the current regimen This situation has led to the emergence of a new paradigm in TB drug discovery that involves therapeutic modulation of host cell functions in order to improve pathogen eradication, namely, host-directed therapy (HDT) [6]. It is uncertain whether inhibition of intracellular M. tuberculosis growth by TAM is due to direct killing of bacteria or to modulation of bactericidal activity of macrophages It remains to be elucidated whether other SERMs exhibit similar antimycobacterial effects in human macrophages. We found that BZA efficiently inhibits intracellular M. tuberculosis growth in human macrophages
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