Modular Chemical Synthesis of Streptogramin and Lankacidin Antibiotics
文献类型：期刊论文
| 作者 | Cai, Lingchao2; Seiple, Ian B.1,4; Li, Qi3 |
| 刊名 | ACCOUNTS OF CHEMICAL RESEARCH
 |
| 出版日期 | 2021-04-20 |
| 卷号 | 54期号:8页码:1891-1908 |
| ISSN号 | 0001-4842 |
| DOI | 10.1021/acs.accounts.0c00894 |
| 通讯作者 | Seiple, Ian B.(ian.seiple@ucsf.edu) ; Li, Qi(qi.li@simm.ac.cn) |
| 英文摘要 | CONSPECTUS: Continued, rapid development of antimicrobial resistance has become worldwide health crisis and a burden on the global economy. Decisive and comprehensive action is required to slow down the spread of antibiotic resistance, including increased investment in antibiotic discovery, sustainable policies that provide returns on investment for newly launched antibiotics, and public education to reduce the overusage of antibiotics, especially in livestock and agriculture. Without significant changes in the current antibiotic pipeline, we are in danger of entering a post-antibiotic era. In this Account, we summarize our recent efforts to develop nextgeneration streptogramin and lankacidin antibiotics that overcome bacterial resistance by means of modular chemical synthesis. First, we describe our highly modular, scalable route to four natural group A streptogramins antibiotics in 6-8 steps from seven simple chemical building blocks. We next describe the application of this route to the synthesis of a novel library of streptogramin antibiotics informed by in vitro and in vivo biological evaluation and high-resolution cryo-electron microscopy. One lead compound showed excellent inhibitory activity in vitro and in vivo against a longstanding streptogramin-resistance mechanism, virginiamycin acetyltransferase. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms. Second, we recount our modular approaches toward lankacidin antibiotics. Lankacidins are a group of polyketide natural products with activity against several strains of Gram-positive bacteria but have not been deployed as therapeutics due to their chemical instability. We describe a route to several diastereomers of 2,18-seco-lankacidinol B in a linear sequence of <= 8 steps from simple building blocks, resulting in a revision of the C4 stereochemistry. We next detail our modular synthesis of several diastereoisomers of iso-lankacidinol that resulted in the structural reassignment of this natural product. These structural revisions raise interesting questions about the biosynthetic origin of lankacidins, all of which possessed uniform stereochemistry prior to these findings. Finally, we summarize the ability of several iso- and seco-lankacidins to inhibit the growth of bacteria and to inhibit translation in vitro, providing important insights into structure-function relationships for the class. |
| WOS关键词 | VIRGINIAMYCIN |
| 资助项目 | National Institute of General Medical Sciences of the National Institutes of Health (NIH)[R35GM128656] ; National Science Foundation of China[22001124] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000643542200008 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/296576]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Seiple, Ian B.; Li, Qi |
| 作者单位 | 1.Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA 2.Nanjing Forestry Univ, Jiangsu Key Lab Biomass Based Green Fuels & Chem, Jiangsu Coinnovat Ctr Efficient Proc & Utilizat F, Jiangsu Prov Key Lab Chem & Utilizat Agroforest B, Nanjing 210037, Jiangsu, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA |
| 推荐引用方式 GB/T 7714 | Cai, Lingchao,Seiple, Ian B.,Li, Qi. Modular Chemical Synthesis of Streptogramin and Lankacidin Antibiotics[J]. ACCOUNTS OF CHEMICAL RESEARCH,2021,54(8):1891-1908. |
| APA | Cai, Lingchao,Seiple, Ian B.,&Li, Qi.(2021).Modular Chemical Synthesis of Streptogramin and Lankacidin Antibiotics.ACCOUNTS OF CHEMICAL RESEARCH,54(8),1891-1908. |
| MLA | Cai, Lingchao,et al."Modular Chemical Synthesis of Streptogramin and Lankacidin Antibiotics".ACCOUNTS OF CHEMICAL RESEARCH 54.8(2021):1891-1908. |
入库方式： OAI收割
来源：上海药物研究所
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