Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy
Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy
复制标题
巴多昔芬通过增强自噬抑制细胞内结核分枝杆菌的生长
DOI：
10.1128/msphere.00124-20
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发表时间：
2020
期刊：
影响因子：
4.8
通讯作者：
Chen Xinchun
中科院分区：
文献类型：
--
作者：
Ouyang Qi;Zhang Kehong;Lin Dachuan;Feng Carl G.;Cai Yi;Chen Xinchun
结核病（TB）仍然是由结核分枝杆菌感染引起的头号杀手。显然需要新的结核病治疗策略。据报道，他莫昔芬，已知作为一种选择性雌激素受体调节剂（SERM），具有抗分枝杆菌活性，并抑制M。结核菌在巨噬细胞中生长。然而，这种抗微生物活性是否是所有SERM的一般性质以及它是如何工作的仍然是未知的。在这项研究中，我们发现，bazedoxifene（BZA），一个新的SERM，抑制细胞内M。结核菌在巨噬细胞中生长。BZA处理增加M.结核病感染的巨噬细胞。我们进一步证明了BZA对自噬的增强依赖于活性氧（ROS）产生的增加，并与Akt/mTOR信号的磷酸化相关。总之，我们的数据揭示了BZA以前未被认识到的抗微生物功能，并表明未来的研究集中在巨噬细胞中SERMs的作用机制上，可能会导致新的针对TB的宿主导向疗法。重要信息由于目前治疗耐多药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）的策略疗效低且副作用大，研究新的治疗方法，包括新药，对于治愈耐药结核病至关重要。宿主定向治疗（HDT）已成为一种很有前途的想法，以调节宿主细胞的反应，以增强对病原体的保护性免疫。苯多昔芬（BZA）是新一代SERM的一种，具有抑制M.结核病在巨噬细胞中存在，并与自噬有关。我们的研究结果揭示了BZA以前未被认识到的抗菌功能。我们认为，SERMs在巨噬细胞中的作用机制可能为针对TB的宿主导向疗法提供新的潜在措施。
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.IMPORTANCESince 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.