Abstract | BACKGROUND: OBJECTIVES AND METHODS: We have used high resolution magic angle spinning-NMR (HRMAS-NMR) to follow ethionamide activation directly within living mycobacterial cells. RESULTS: Data indicated that the intracellular metabolization of ethionamide strictly depends on the presence of the monooxygenase EthA and that EthA-dependent activation of ethionamide is coupled to a precise molecular sorting mechanism of the ethionamide metabolites. We found that the previously identified ethionamide metabolite 2-ethyl-4-hydroxymethylpyridine is produced in substantial amounts by the ethionamide-treated mycobacteria and that it is present exclusively outside of the bacteria. In contrast, the still unidentified ethionamide metabolite ETH* is the only ethionamide derivative detected within the bacterial cell. Moreover, ETH* appears to be unable to cross the bacterial envelope and consequently accumulates within the cytoplasm of the ethionamide-treated mycobacteria. CONCLUSIONS: These results strongly suggest that ETH* is the active antimycobacterial ethionamide derivative and open new perspectives for the understanding of the mode of action of prodrugs.
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Authors | Xavier Hanoulle, Jean-Michel Wieruszeski, Pierre Rousselot-Pailley, Isabelle Landrieu, Camille Locht, Guy Lippens, Alain R Baulard |
Journal | The Journal of antimicrobial chemotherapy
(J Antimicrob Chemother)
Vol. 58
Issue 4
Pg. 768-72
(Oct 2006)
ISSN: 0305-7453 [Print] England |
PMID | 16895935
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Bacterial Proteins
- Culture Media
- Prodrugs
- etaA protein, Mycobacterium tuberculosis
- Oxygenases
- Ethionamide
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Topics |
- Bacterial Proteins
(metabolism)
- Biotransformation
- Culture Media
- Ethionamide
(chemistry, metabolism)
- Humans
- Magnetic Resonance Spectroscopy
(instrumentation, methods)
- Mycobacterium smegmatis
(growth & development, metabolism)
- Oxygenases
(metabolism)
- Prodrugs
(chemistry, metabolism)
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