Design, synthesis, and study of a mycobactin-artemisinin conjugate that has selective and potent activity against tuberculosis and malaria.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Miller, MJ; Walz, AJ; Zhu, H; Wu, C; Moraski, G; Möllmann, U; Tristani, EM; Crumbliss, AL; Ferdig, MT; Checkley, L; Edwards, RL; Boshoff, HI

Published Date

  • February 2011

Published In

Volume / Issue

  • 133 / 7

Start / End Page

  • 2076 - 2079

PubMed ID

  • 21275374

Pubmed Central ID

  • 21275374

Electronic International Standard Serial Number (EISSN)

  • 1520-5126

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja109665t

Language

  • eng