文献类型：期刊文献

英文题名：Generation of Fluorinated Amychelin Siderophores against Pseudomonas aeruginosa Infections by a Combination of Genome Mining and Mutasynthesis

作者：Xie, Feng[1];Dai, Shengwang[3];Zhao, Yu[3];Huang, Pei[3];Yu, Shen[4];Ren, Biao[5,6];Wang, Qiushui[3];Ji, Zengchun[3];Alterovitz, Gil[7];Zhang, Qi[8];Zhang, Jingyu[2];Chen, Xiangyin[2];Jiang, Lan[2];Song, Fuhang[3];Liu, Hongwei[1];Ausubel, Frederick M.[4];Liu, Xueting[2];Dai, Huanqin[1];Zhang, Lixin[2]

机构：[1]Chinese Acad Sci, Inst Microbiol, State Key Lab Mycol, Beijing 100101, Peoples R China;[2]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[3]Chinese Acad Sci, Key Lab Pathogen Microbiol & Immunol, Inst Microbiol, Beijing 100101, Peoples R China;[4]Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA;[5]Sichuan Univ, State Key Lab Oral Dis, Chengdu 610041, Sichuan, Peoples R China;[6]Sichuan Univ, Natl Clin Res Ctr Oral Dis, Chengdu 610041, Sichuan, Peoples R China;[7]Boston Childrens Hosp, Boston, MA 02115 USA;[8]Peking Univ, Dept Pediat, China Japan Friendship Sch Clin Med, Beijing 100029, Peoples R China

年份：2020

卷号：27

期号：12

起止页码：1532

外文期刊名：CELL CHEMICAL BIOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000600019000008)】；

基金：We gratefully acknowledge the financial support from the National Natural Science Foundation of China (21877124, 31720103901, 81573341, 31600017, 31320103911), the National Key Research and Development Program of China (2019YFA0906200), the Open Project Funding of the State Key Laboratory of Bioreactor Engineering, the 111 Project (B18022), the National Key R&D Program of China (2017YFE0108200).

语种：英文

摘要：Pioneering microbial genomic surveys have revealed numerous untapped biosynthetic gene clusters, unveiling the great potential of new natural products. Here, using a combination of genome mining, mutasynthesis, and activity screening in an infection model comprising Caenorhabditis elegans and Pseudomonas aeruginosa, we identified candidate virulence-blocking amychelin siderophore compounds from actinomycetes. Subsequently, we developed unreported analogs of these virulence-blocking siderophores with improved potency by exploiting an Amycolatopsis methanolica strain 239(T) chorismate to salicylate a biosynthetic sub-pathway for mutasynthesis. This allowed us to generate the fluorinated amychelin, fluoroamychelin I, which rescued C. elegans from P. aeruginosa-mediated killing with an EC50 value of 1.4 mM, outperforming traditional antibiotics including ceftazidime and meropenem. In general, this paper describes an efficient platform for the identification and production of classes of anti-microbial compounds with potential unique modes of action.