Design, Synthesis, and Study of a Mycobactin鈭扐rtemisinin Conjugate That Has Selective and Potent Activity against Tuberculosis and Malaria

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• 作者：Marvin J. Miller ; Andrew J. Walz ; Helen Zhu ; Chunrui Wu ; Garrett Moraski ; Ute M枚llmann ; Esther M. Tristani ; Alvin L. Crumbliss ; Michael T. Ferdig ; Lisa Checkley ; Rachel L. Edwards ; Helena I. Boshoff
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：February 23, 2011
• 年：2011
• 卷：133
• 期：7
• 页码：2076-2079
• 全文大小：778K
• 年卷期：v.133,no.7(February 23, 2011)
• ISSN：1520-5126

文摘

Although the antimalarial agent artemisinin itself is not active against tuberculosis, conjugation to a mycobacterial-specific siderophore (microbial iron chelator) analogue induces significant and selective antituberculosis activity, including activity against multi- and extensively drug-resistant strains of Mycobacterium tuberculosis. The conjugate also retains potent antimalarial activity. Physicochemical and whole-cell studies indicated 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 鈥淭rojan horse鈥?approach demonstrates that new pathogen-selective therapeutic agents in which the iron component of the delivery vehicle also participates in triggering the antibiotic activity can be generated. The result is that one appropriate conjugate has potent and selective activity against two of the most deadly diseases in the world.