Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea.
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, South Korea; Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon, South Korea; Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea.
Biomed Pharmacother. 2024 Oct;179:117313. doi: 10.1016/j.biopha.2024.117313. Epub 2024 Aug 20.
Mycobacteroides abscessus (Mabc) is a rapidly growing nontuberculous mycobacterium that poses a considerable challenge as a multidrug-resistant pathogen causing chronic human infection. Effective therapeutics that enhance protective immune responses to Mabc are urgently needed. This study introduces trans-3,5,4'-trimethoxystilbene (V46), a novel resveratrol analogue with autophagy-activating properties and antimicrobial activity against Mabc infection, including multidrug-resistant strains. Among the resveratrol analogues tested, V46 significantly inhibited the growth of both rough and smooth Mabc strains, including multidrug-resistant strains, in macrophages and in the lungs of mice infected with Mabc. Additionally, V46 substantially reduced Mabc-induced levels of pro-inflammatory cytokines and chemokines in both macrophages and during in vivo infection. Mechanistic analysis showed that V46 suppressed the activation of the protein kinase B/Akt-mammalian target of rapamycin signaling pathway and enhanced adenosine monophosphate-activated protein kinase signaling in Mabc-infected cells. Notably, V46 activated autophagy and the nuclear translocation of transcription factor EB, which is crucial for antimicrobial host defenses against Mabc. Furthermore, V46 upregulated genes associated with autophagy and lysosomal biogenesis in Mabc-infected bone marrow-derived macrophages. The combination of V46 and rifabutin exerted a synergistic antimicrobial effect. These findings identify V46 as a candidate host-directed therapeutic for Mabc infection that activates autophagy and lysosomal function via transcription factor EB.
脆弱拟杆菌（Mabc）是一种快速生长的非结核分枝杆菌，作为一种导致慢性人类感染的多药耐药病原体，构成了相当大的挑战。迫切需要能够增强针对 Mabc 的保护性免疫反应的有效疗法。本研究介绍了反式-3,5,4'-三甲氧基二苯乙烯（V46），这是一种新型白藜芦醇类似物，具有自噬激活特性和抗 Mabc 感染的抗菌活性，包括多药耐药株。在测试的白藜芦醇类似物中，V46 显著抑制了粗糙和光滑 Mabc 株，包括多药耐药株，在巨噬细胞中和感染 Mabc 的小鼠肺部中的生长。此外，V46 大大降低了 Mabc 诱导的巨噬细胞和体内感染过程中促炎细胞因子和趋化因子的水平。机制分析表明，V46 抑制了 Mabc 感染细胞中蛋白激酶 B/Akt-雷帕霉素靶蛋白信号通路的激活，并增强了腺苷单磷酸激活蛋白激酶信号。值得注意的是，V46 激活了自噬和转录因子 EB 的核易位，这对于针对 Mabc 的抗菌宿主防御至关重要。此外，V46 上调了 Mabc 感染骨髓来源的巨噬细胞中与自噬和溶酶体发生相关的基因。V46 和利福布汀的联合使用发挥了协同的抗菌作用。这些发现确定了 V46 作为一种宿主导向的治疗 Mabc 感染的候选药物，通过转录因子 EB 激活自噬和溶酶体功能。
