Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 133, Issue 7, Pages 2076-2079Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja109665t
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Funding
- U.S. National Institutes of Health [R01 AI054193, AI055035]
- NSF [CHE 0809466]
- NIH, NIAID
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [0809466] Funding Source: National Science Foundation
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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 anti-tuberculosis 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.
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