Design, synthesis, and study of a mycobactin-artemisinin conjugate that has selective and potent activity against tuberculosis and malaria.
Design, synthesis, and study of a mycobactin-artemisinin conjugate that has selective and potent activity against tuberculosis and malaria.
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DOI：
10.1021/ja109665t
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发表时间：
2011-02-23
影响因子：
15
通讯作者：
Boshoff HI
中科院分区：
文献类型：
--
作者：
Miller MJ;Walz AJ;Zhu H;Wu C;Moraski G;Möllmann U;Tristani EM;Crumbliss AL;Ferdig MT;Checkley L;Edwards RL;Boshoff HI
尽管抗疟剂青蒿素本身对结核病没有活性，但与分枝杆菌特异性铁载体（微生物铁螯合剂）类似物的缀合诱导显著和选择性的抗结核病活性，包括针对Mtb的MDR和XDR菌株的活性。该缀合物还保留了有效的抗疟疾活性。物理化学和全细胞研究表明，铁还原为亚铁的铁复合物的共轭物启动预期的杀菌芬顿型自由基化学青蒿素组分。因此，这种“特洛伊木马”方法表明，可以产生新的病原体选择性治疗剂，其中递送载体的铁组分也参与触发抗生素活性。结果是，一种合适的缀合物对世界上两种最致命的疾病具有有效和选择性的活性。
Although the antimalarial agent, artemisinin itself is not active against tuberculosis, conjugation to a mycobacterial specific siderophore (microbial iron chelator) analog induces significant and selective anti-tuberculosis activity, including activity against MDR and XDR strains of Mtb. The conjugate also retains potent antimalarial activity. Physicochemical and whole cell studies indicate that ferric to ferrous reduction of the iron complex of the conjugate initiates the expected bactericidal Fenton-type radical chemistry on the artemisinin component. Thus, this “Trojan Horse” approach demonstrates that new pathogen selective therapeutic agents can be generated in which the iron component of the delivery vehicle also participates in triggering the antibiotic activity. The result is that one appropriate conjugate has potent and selective activity against two of the most deadly diseases in the world.
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影响因子：
7.3
作者：
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通讯作者：
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