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

2011; American Chemical Society; Volume: 133; Issue: 7 Linguagem: Inglês

10.1021/ja109665t

1943-2984

Marvin J. Miller, Andrew J. Walz, Helen He Zhu, Chunrui Wu, Garrett C. Moraski, Ute Möllmann, Esther M. Tristani, Alvin L. Crumbliss, Michael T. Ferdig, Lisa A. Checkley, Rachel L. Edwards, Helena I. Boshoff,

Cancer therapeutics and mechanisms

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 "Trojan horse" 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.