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JAC Advance Access published online on August 8, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl332
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received May 16, 2006
Revised July 4, 2006
Accepted July 18, 2006

Original article

Selective intracellular accumulation of the major metabolite issued from the activation of the prodrug ethionamide in mycobacteria

Xavier Hanoulle 1 {dagger}, Jean-Michel Wieruszeski 2, Pierre Rousselot-Pailley 2, Isabelle Landrieu 2, Camille Locht 3, Guy Lippens 2 {ddagger}, and Alain R. Baulard 3 * {ddagger}

1 UMR 8525 CNRS-Universíté de Lille 2, Lille, F-59021, France; Present address. Department of Medical Protein Research (VIB09), Flanders Interuniversity Institute for Biotechnology, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, B-9000 Gent, Belgium
2 UMR 8525 CNRS-Universíté de Lille 2, Lille, F-59021, France
3 U629 INSERM-Institut Pasteur de Lille, F-59021, France

* To whom correspondence should be addressed.
Alain R. Baulard, E-mail: Alain.Baulard{at}pasteur-lille.fr


  Abstract

Background: Ethionamide is one of the most widely used drugs for the treatment of multidrug-resistant tuberculosis (MDR-TB). Like isoniazid, and pyrazinamide, ethionamide is a prodrug that needs to be activated by a mycobacterial enzyme. Activation pathways of prodrugs are generally problematic to uncover as they produce intermediates potentially difficult to characterize, to purify and that might prove unstable outside of their cellular context.

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.

Keywords: HRMAS-NMR; thioamide; tuberculosis.
{ddagger}These authors contributed equally to this work.
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