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Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis
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| Zeitschriftentitel: | Proceedings of the National Academy of Sciences |
|---|---|
| Personen und Körperschaften: | , , , , |
| In: | Proceedings of the National Academy of Sciences, 97, 2000, 17, S. 9677-9682 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Proceedings of the National Academy of Sciences
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| Schlagwörter: |
| author_facet |
DeBarber, Andrea E. Mdluli, Khisimuzi Bosman, Marlein Bekker, Linda-Gail Barry, Clifton E. DeBarber, Andrea E. Mdluli, Khisimuzi Bosman, Marlein Bekker, Linda-Gail Barry, Clifton E. |
|---|---|
| author |
DeBarber, Andrea E. Mdluli, Khisimuzi Bosman, Marlein Bekker, Linda-Gail Barry, Clifton E. |
| spellingShingle |
DeBarber, Andrea E. Mdluli, Khisimuzi Bosman, Marlein Bekker, Linda-Gail Barry, Clifton E. Proceedings of the National Academy of Sciences Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis Multidisciplinary |
| author_sort |
debarber, andrea e. |
| spelling |
DeBarber, Andrea E. Mdluli, Khisimuzi Bosman, Marlein Bekker, Linda-Gail Barry, Clifton E. 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.97.17.9677 <jats:p> Ethionamide (ETA) is an important component of second-line therapy for the treatment of multidrug-resistant tuberculosis. Synthesis of radiolabeled ETA and an examination of drug metabolites formed by whole cells of <jats:italic>Mycobacterium tuberculosis</jats:italic> (MTb) have allowed us to demonstrate that ETA is activated by <jats:italic>S</jats:italic> -oxidation before interacting with its cellular target. ETA is metabolized by MTb to a 4-pyridylmethanol product remarkably similar in structure to that formed by the activation of isoniazid by the catalase-peroxidase KatG. We have demonstrated that overproduction of Rv3855 (EtaR), a putative regulatory protein from MTb, confers ETA resistance whereas overproduction of an adjacent, clustered monooxygenase (Rv3854c, EtaA) confers ETA hypersensitivity. Production of EtaA appears to be negatively regulated by EtaR and correlates directly with [ <jats:sup>14</jats:sup> C]ETA metabolism, suggesting that EtaA is the activating enzyme responsible for thioamide oxidation and subsequent toxicity. Coding sequence mutations in EtaA were found in 11 of 11 multidrug-resistant MTb patient isolates from Cape Town, South Africa. These isolates showed broad cross-resistance to thiocarbonyl containing drugs including ETA, thiacetazone, and thiocarlide. </jats:p> Ethionamide activation and sensitivity in multidrug-resistant <i>Mycobacterium tuberculosis</i> Proceedings of the National Academy of Sciences |
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| title |
Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| title_unstemmed |
Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| title_full |
Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| title_fullStr |
Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| title_full_unstemmed |
Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| title_short |
Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| title_sort |
ethionamide activation and sensitivity in multidrug-resistant
<i>mycobacterium tuberculosis</i> |
| topic |
Multidisciplinary |
| url |
http://dx.doi.org/10.1073/pnas.97.17.9677 |
| publishDate |
2000 |
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9677-9682 |
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<jats:p>
Ethionamide (ETA) is an important component of second-line therapy for the treatment of multidrug-resistant tuberculosis. Synthesis of radiolabeled ETA and an examination of drug metabolites formed by whole cells of
<jats:italic>Mycobacterium tuberculosis</jats:italic>
(MTb) have allowed us to demonstrate that ETA is activated by
<jats:italic>S</jats:italic>
-oxidation before interacting with its cellular target. ETA is metabolized by MTb to a 4-pyridylmethanol product remarkably similar in structure to that formed by the activation of isoniazid by the catalase-peroxidase KatG. We have demonstrated that overproduction of Rv3855 (EtaR), a putative regulatory protein from MTb, confers ETA resistance whereas overproduction of an adjacent, clustered monooxygenase (Rv3854c, EtaA) confers ETA hypersensitivity. Production of EtaA appears to be negatively regulated by EtaR and correlates directly with [
<jats:sup>14</jats:sup>
C]ETA metabolism, suggesting that EtaA is the activating enzyme responsible for thioamide oxidation and subsequent toxicity. Coding sequence mutations in EtaA were found in 11 of 11 multidrug-resistant MTb patient isolates from Cape Town, South Africa. These isolates showed broad cross-resistance to thiocarbonyl containing drugs including ETA, thiacetazone, and thiocarlide.
</jats:p> |
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| author | DeBarber, Andrea E., Mdluli, Khisimuzi, Bosman, Marlein, Bekker, Linda-Gail, Barry, Clifton E. |
| author_facet | DeBarber, Andrea E., Mdluli, Khisimuzi, Bosman, Marlein, Bekker, Linda-Gail, Barry, Clifton E., DeBarber, Andrea E., Mdluli, Khisimuzi, Bosman, Marlein, Bekker, Linda-Gail, Barry, Clifton E. |
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| description | <jats:p> Ethionamide (ETA) is an important component of second-line therapy for the treatment of multidrug-resistant tuberculosis. Synthesis of radiolabeled ETA and an examination of drug metabolites formed by whole cells of <jats:italic>Mycobacterium tuberculosis</jats:italic> (MTb) have allowed us to demonstrate that ETA is activated by <jats:italic>S</jats:italic> -oxidation before interacting with its cellular target. ETA is metabolized by MTb to a 4-pyridylmethanol product remarkably similar in structure to that formed by the activation of isoniazid by the catalase-peroxidase KatG. We have demonstrated that overproduction of Rv3855 (EtaR), a putative regulatory protein from MTb, confers ETA resistance whereas overproduction of an adjacent, clustered monooxygenase (Rv3854c, EtaA) confers ETA hypersensitivity. Production of EtaA appears to be negatively regulated by EtaR and correlates directly with [ <jats:sup>14</jats:sup> C]ETA metabolism, suggesting that EtaA is the activating enzyme responsible for thioamide oxidation and subsequent toxicity. Coding sequence mutations in EtaA were found in 11 of 11 multidrug-resistant MTb patient isolates from Cape Town, South Africa. These isolates showed broad cross-resistance to thiocarbonyl containing drugs including ETA, thiacetazone, and thiocarlide. </jats:p> |
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| spelling | DeBarber, Andrea E. Mdluli, Khisimuzi Bosman, Marlein Bekker, Linda-Gail Barry, Clifton E. 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.97.17.9677 <jats:p> Ethionamide (ETA) is an important component of second-line therapy for the treatment of multidrug-resistant tuberculosis. Synthesis of radiolabeled ETA and an examination of drug metabolites formed by whole cells of <jats:italic>Mycobacterium tuberculosis</jats:italic> (MTb) have allowed us to demonstrate that ETA is activated by <jats:italic>S</jats:italic> -oxidation before interacting with its cellular target. ETA is metabolized by MTb to a 4-pyridylmethanol product remarkably similar in structure to that formed by the activation of isoniazid by the catalase-peroxidase KatG. We have demonstrated that overproduction of Rv3855 (EtaR), a putative regulatory protein from MTb, confers ETA resistance whereas overproduction of an adjacent, clustered monooxygenase (Rv3854c, EtaA) confers ETA hypersensitivity. Production of EtaA appears to be negatively regulated by EtaR and correlates directly with [ <jats:sup>14</jats:sup> C]ETA metabolism, suggesting that EtaA is the activating enzyme responsible for thioamide oxidation and subsequent toxicity. Coding sequence mutations in EtaA were found in 11 of 11 multidrug-resistant MTb patient isolates from Cape Town, South Africa. These isolates showed broad cross-resistance to thiocarbonyl containing drugs including ETA, thiacetazone, and thiocarlide. </jats:p> Ethionamide activation and sensitivity in multidrug-resistant <i>Mycobacterium tuberculosis</i> Proceedings of the National Academy of Sciences |
| spellingShingle | DeBarber, Andrea E., Mdluli, Khisimuzi, Bosman, Marlein, Bekker, Linda-Gail, Barry, Clifton E., Proceedings of the National Academy of Sciences, Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis, Multidisciplinary |
| title | Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| title_full | Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| title_fullStr | Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| title_full_unstemmed | Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| title_short | Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| title_sort | ethionamide activation and sensitivity in multidrug-resistant <i>mycobacterium tuberculosis</i> |
| title_unstemmed | Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis |
| topic | Multidisciplinary |
| url | http://dx.doi.org/10.1073/pnas.97.17.9677 |