Zheng Qingfei, Wang Qinglan, Wang Shoufeng, Wu Jiequn, Gao Qian, Liu Wen
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Key Laboratory of Medical Molecular Virology, Institutes of Biomedical Sciences and Institute of Medical Microbiology, Shanghai Medical College, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, China.
Chem Biol. 2015 Aug 20;22(8):1002-7. doi: 10.1016/j.chembiol.2015.06.019. Epub 2015 Jul 23.
Thiostrepton (TSR) is an archetypal thiopeptide antibiotic possessing a quinaldic acid (QA) moiety in the side ring system. According to the mechanism of TSR previously known to target bacterial ribosome, we recently designed and biosynthesized several TSR derivatives that varied in QA substitution. Utilizing these thiopeptide antibiotics to treat the intracellular pathogen Mycobacterium marinum, we herein report a novel mode of action of TSRs, which induce ER stress-mediated autophagy to enhance host cell defense. This intracellular response, which is sensitive to the modification of the QA group, serves as an indirect but unignorable mechanism for eliminating intracellular pathogens. TSRs are thus the only type of antibiotics, to our knowledge, with the dual action on both the parasitic bacteria and the infected host cells. The newly observed mechanism of TSRs may inspire the future change in the treatment of intracellular pathogens, by taking host response into account.
硫链丝菌素（TSR）是一种典型的硫肽类抗生素，其侧环系统中含有喹哪啶酸（QA）部分。根据先前已知的TSR靶向细菌核糖体的机制，我们最近设计并生物合成了几种在QA取代方面有所不同的TSR衍生物。利用这些硫肽类抗生素治疗细胞内病原体海分枝杆菌，我们在此报告了TSR的一种新作用模式，即诱导内质网应激介导的自噬以增强宿主细胞防御。这种对QA基团修饰敏感的细胞内反应是消除细胞内病原体的一种间接但不可忽视的机制。据我们所知，TSR是唯一一类对寄生细菌和受感染宿主细胞都有双重作用的抗生素。TSR新观察到的机制可能会促使未来在考虑宿主反应的情况下改变细胞内病原体的治疗方法。
