Wu Yang, Yang Xuefei, Zhang Dongdong, Lu Chunhua
Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Key Laboratory of Economic Plants and Biotechnology, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
Front Microbiol. 2020 Sep 25;11:571217. doi: 10.3389/fmicb.2020.571217. eCollection 2020.
The type III secretion system (T3SS) consists of a syringe-like export machine injecting effectors from the bacterial cytosol directly into host cells to establish infection. This mechanism is widely distributed in gram-negative bacteria and can be targeted as an innovative strategy for the developing of anti-virulence drugs. In this study, we present an effective T3SS inhibitor, myricanol, inspired by the use of folk medicinal plants traditionally used against infections. Myricanol is a cyclic diarylheptanoid isolated from the medicinal plant , which is found in South and East Asia. Bioassay-guided fractionation revealed that myricanol inhibited not only the secretion of type III effector proteins of serovar Typhimurium UK-1 χ8956 (. Typhimurium) but also the invasion of . Typhimurium into mammalian cells, but showed no toxicity to bacterial growth or the host cells. RNA-Seq data analysis showed that the transcription of the pathogenesis-related SPI-1 gene was significantly inhibited by myricanol. Further study demonstrated that myricanol binds physically to HilD and interferes with its DNA-binding activity to the promoters of the and genes. In conclusion, we propose that myricanol is responsible for the anti-infectious properties of and is a novel T3SS inhibitor of . Typhimurium through a previously unappreciated mechanism of action.
III型分泌系统（T3SS）由一个类似注射器的输出装置组成，该装置将细菌胞质溶胶中的效应蛋白直接注入宿主细胞以建立感染。这种机制广泛存在于革兰氏阴性菌中，可作为开发抗毒力药物的创新策略的靶点。在本研究中，我们提出了一种有效的T3SS抑制剂——杨梅素，它的灵感来源于传统上用于抗感染的民间药用植物。杨梅素是从东亚和南亚的药用植物中分离出的一种环状二芳基庚烷。生物测定导向的分级分离显示，杨梅素不仅抑制鼠伤寒沙门氏菌UK-1 χ8956（鼠伤寒沙门氏菌）III型效应蛋白的分泌，还抑制鼠伤寒沙门氏菌对哺乳动物细胞的侵袭，但对细菌生长或宿主细胞无毒性。RNA测序数据分析表明，杨梅素显著抑制了与致病相关的SPI-1基因的转录。进一步的研究表明，杨梅素与HilD物理结合，并干扰其与prgH和invF基因启动子的DNA结合活性。总之，我们认为杨梅素具有抗感染特性，并且是通过一种前所未有的作用机制成为鼠伤寒沙门氏菌新型T3SS抑制剂。
