文献类型：期刊文献

英文题名：Chrysomycin A Derivatives for the Treatment of Multi-Drug-Resistant Tuberculosis

作者：Wu, Fan[1,2];Zhang, Jing[1,2];Song, Fuhang[3];Wang, Sanshan[1,2];Guo, Hui[3];Wei, Qi[3];Dai, Huanqin[3];Chen, Xiangyin[4];Xia, Xuekui[4,5];Liu, Xueting[4];Zhang, Lixin[3,4,5];Yu, Jin-Quan[6];Lei, Xiaoguang[1,2]

机构：[1]Peking Univ, Beijing Natl Lab Mol Sci, Key Lab Bioorgan Chem & Mol Engn,Minist Educ, Synthet & Funct Biomol Ctr,Coll Chem & Mol Engn,D, Beijing 100871, Peoples R China;[2]Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China;[3]Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing 100101, Peoples R China;[4]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[5]Qilu Univ Technol, Shandong Acad Sci, Biol Inst, Key Biosensor Lab Shandong Prov, Jinan 250013, Peoples R China;[6]Scripps Res Inst, La Jolla, CA 92037 USA

年份：2020

卷号：6

期号：6

起止页码：928

外文期刊名：ACS CENTRAL SCIENCE

收录：;EI(收录号：20202008661791);WOS:【SCI-EXPANDED(收录号:WOS:000543781200015)】；

基金：We thank Dr. Benke Hong, Dr. Hiu Chun Lam, and Prof. Seth Herzon (Yale University) for helpful discussions. Financial support from the National Natural Science Foundation of China (21625201, 21961142010, 21661140001, 91853202, and 21521003 to X. Lei; 31430002 and 31720103901 to L. Zhang), the National Key Research and Development Program of China (2017YFA0505200 to X. Lei), the Beijing Outstanding Young Scientist Program (BJJWZYJH01201910001001 to X. Lei), and Peking-Tsinghua Center for Life Science is gratefully acknowledged.

语种：英文

摘要：Tuberculosis (TB) is a life-threatening disease resulting in an estimated 10 million new infections and 1.8 million deaths annually, primarily in underdeveloped countries. The economic burden of TB has been estimated as approximately 12 billion USD annually in direct and indirect costs. Additionally, multi-drug-resistant (MDR) and extreme-drug-resistant (XTR) TB strains resulting in about 250 000 deaths annually are now widespread, increasing pressure on the identification of new anti-TB agents that operate by a novel mechanism of action. Chrysomycin A is a rare C-aryl glycoside first discovered over 60 years ago. In a recent high-throughput screen, we found that chrysomycin A has potent anti-TB activity, with minimum inhibitory concentration (MIC) = 0.4 pg/mL against MDR-TB strains. However, chrysomycin A is obtained in low yields from fermentation of Streptomyces, and the mechanism of action of this compound is unknown. To facilitate the mechanism of action and preclinical studies of chrysomycin A, we developed a 10-step, scalable synthesis of the isolate and its two natural congeners polycarcin V and gilvocarcin V. The synthetic sequence was enabled by the implementation of two sequential C-H functionalization steps as well as a late-stage C-glycosylation. In addition, >10 g of the advanced synthetic intermediate has been prepared, which greatly facilitated the synthesis of 33 new analogues to date. The structure-activity relationship was subsequently delineated, leading to the identification of derivatives with superior potency against MDR-TB (MIC = 0.08 mu g/mL). The more potent derivatives contained a modified carbohydrate residue which suggests that further optimization is additionally possible. The chemistry we report here establishes a platform for the development of a novel class of anti-TB agents active against drug-resistant pathogens.