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Chemical Genomics, Structure Elucidation, and in Vivo Studies of the Marine-Derived Anticlostridial Ecteinamycin
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-07-26 00:00:00 , DOI: 10.1021/acschembio.7b00388 Thomas P. Wyche 1 , René F. Ramos Alvarenga 1 , Jeff S. Piotrowski 2 , Megan N. Duster 3 , Simone R. Warrack 3 , Gabriel Cornilescu 4 , Travis J. De Wolfe 5 , Yanpeng Hou 1 , Doug R. Braun 1 , Gregory A. Ellis 1 , Scott W. Simpkins 6 , Justin Nelson 6 , Chad L. Myers 6 , James Steele 5 , Hirotada Mori 7 , Nasia Safdar 3 , John L. Markley 4 , Scott R. Rajski 1 , Tim S. Bugni 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-07-26 00:00:00 , DOI: 10.1021/acschembio.7b00388 Thomas P. Wyche 1 , René F. Ramos Alvarenga 1 , Jeff S. Piotrowski 2 , Megan N. Duster 3 , Simone R. Warrack 3 , Gabriel Cornilescu 4 , Travis J. De Wolfe 5 , Yanpeng Hou 1 , Doug R. Braun 1 , Gregory A. Ellis 1 , Scott W. Simpkins 6 , Justin Nelson 6 , Chad L. Myers 6 , James Steele 5 , Hirotada Mori 7 , Nasia Safdar 3 , John L. Markley 4 , Scott R. Rajski 1 , Tim S. Bugni 1
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A polyether antibiotic, ecteinamycin (1), was isolated from a marine Actinomadura sp., cultivated from the ascidian Ecteinascidia turbinata. 13C enrichment, high resolution NMR spectroscopy, and molecular modeling enabled elucidation of the structure of 1, which was validated on the basis of comparisons with its recently reported crystal structure. Importantly, ecteinamycin demonstrated potent activity against the toxigenic strain of Clostridium difficile NAP1/B1/027 (MIC = 59 ng/μL), as well as other toxigenic and nontoxigenic C. difficile isolates both in vitro and in vivo. Additionally, chemical genomics studies using Escherichia coli barcoded deletion mutants led to the identification of sensitive mutants such as trkA and kdpD involved in potassium cation transport and homeostasis supporting a mechanistic proposal that ecteinamycin acts as an ionophore antibiotic. This is the first antibacterial agent whose mechanism of action has been studied using E. coli chemical genomics. On the basis of these data, we propose ecteinamycin as an ionophore antibiotic that causes C. difficile detoxification and cell death via potassium transport dysregulation.
中文翻译：
化学基因组学，结构阐明，和海洋衍生的抗梭菌依特替霉素的体内研究。
从海生猕猴桃（Ecteinascidia turbinata）种植的海洋Actinomadura sp。中分离出了聚醚抗生素ecteinamycin（1）。13 C富集，高分辨率NMR光谱和分子模型能够阐明1的结构，该结构在与最近报道的晶体结构进行比较的基础上得到了验证。重要的是，ecteinamycin在体外和体内均显示出对艰难梭状芽胞杆菌NAP1 / B1 / 027（MIC = 59 ng /μL）以及其他产毒和非产毒梭状芽胞杆菌分离物的有效毒力活性。。此外，使用大肠杆菌条形码缺失删除突变体的化学基因组学研究导致鉴定出敏感突变体，例如参与钾阳离子转运和体内稳态的trkA和kdpD，支持了一种以ecteinamycin作为离子载体抗生素的机制的建议。这是使用大肠杆菌化学基因组学研究其作用机理的第一种抗菌剂。根据这些数据，我们建议将ecteinamycin作为一种离子载体抗生素，通过钾转运失调导致艰难梭菌解毒和细胞死亡。
更新日期：2017-07-28
中文翻译：
化学基因组学，结构阐明，和海洋衍生的抗梭菌依特替霉素的体内研究。
从海生猕猴桃（Ecteinascidia turbinata）种植的海洋Actinomadura sp。中分离出了聚醚抗生素ecteinamycin（1）。13 C富集，高分辨率NMR光谱和分子模型能够阐明1的结构，该结构在与最近报道的晶体结构进行比较的基础上得到了验证。重要的是，ecteinamycin在体外和体内均显示出对艰难梭状芽胞杆菌NAP1 / B1 / 027（MIC = 59 ng /μL）以及其他产毒和非产毒梭状芽胞杆菌分离物的有效毒力活性。。此外，使用大肠杆菌条形码缺失删除突变体的化学基因组学研究导致鉴定出敏感突变体，例如参与钾阳离子转运和体内稳态的trkA和kdpD，支持了一种以ecteinamycin作为离子载体抗生素的机制的建议。这是使用大肠杆菌化学基因组学研究其作用机理的第一种抗菌剂。根据这些数据，我们建议将ecteinamycin作为一种离子载体抗生素，通过钾转运失调导致艰难梭菌解毒和细胞死亡。
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