title: Thiopeptide Antibiotics Exhibit a Dual Mode of Action against Intracellular Pathogens by Affecting Both Host and Microbe.
abstract: 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.
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Qinglan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
authors.forename: Shoufeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Huzhou Center of Bio-Synthetic Innovation, 1366 Hongfeng Road, Huzhou 313000, China.
authors.forename: Jiequn
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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. Electronic address: qgao99@yahoo.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China; Huzhou Center of Bio-Synthetic Innovation, 1366 Hongfeng Road, Huzhou 313000, China. Electronic address: wliu@mail.sioc.ac.cn.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D009165:Mycobacterium Infections, Nontuberculous / Q000188:drug therapy; D019910:Mycobacterium marinum / Q000187:drug effects*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D013312:Stress, Physiological / Q000187:drug effects; D013883:Thiostrepton / Q000138:chemical synthesis / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: D000900:Anti-Bacterial Agents; D011804:Quinolines; D013883:Thiostrepton; C008898:quinaldic acid