The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
Activation of the Pro-drug Ethionamide Is Regulated in Mycobacteria
Open accessAbstract
The anti-tuberculosis drug ethionamide (ETH), which is a structural analog of isoniazid (INH), is known to strongly inhibit mycolic acid synthesis in Mycobacterium tuberculosis. Although several targets have been identified for INH, only speculative information is available concerning ETH. Mutations within the promoter and the coding region of enoyl-acyl carrier protein reductase (InhA) were found to confer resistance to both drugs, thus leading to the impression that INH and ETH may share a common mode of action. However, a notable distinction between the two drugs lies in the lack of cross-resistance in clinical isolates. This may be attributed in part to the fact that the pro-drug INH must be activated via KatG, and no activation step for ETH has yet been described. Here we report the identification of an activator for ETH. The ETH activator (Rv3854c), which we have termed EthA, was found to be homologous to various monooxygenases and induced ETH sensitivity when overexpressed in mycobacteria. Interestingly, the neighboring open reading frame (Rv3855), which was found homologous to transcriptional repressors of the tetR family, led to ETH resistance when overexpressed. In addition, chromosomal inactivation of this gene by transposition led to ETH hypersensitivity. These data strongly suggest that Rv3855, which we have termed EthR, regulates the production of EthA, which subsequently activates the pro-drug ETH. This study opens up new avenues of research relating to ETH activation in mycobacteria, possibly leading to an improved efficacy of ETH and to the generation of new anti-mycobacterial agents.
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Cites
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Cited by
The TetR Family of Transcriptional Repressors
Ramos, J. L., Martínez-Bueno, M., Molina-Henares, A. J., Terán, W., Watanabe, K., Zhang, X., Gallegos, M. T., Brennan, R., & Tobes, R. (2005) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.69.2.326-356.2005 · Cited by 1,103
Cuthbertson, L., & Nodwell, J. R. (2013) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00018-13 · Cited by 554
Rodriguez, G. M., Voskuil, M. I., Gold, B., Schoolnik, G. K., & Smith, I. (2002) · Infection and Immunity · doi:10.1128/iai.70.7.3371-3381.2002 · Cited by 490
Antituberculosis drugs: Ten years of research
Janin, Y. L. (2007) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2007.01.030 · Cited by 485
THE MAGIC BULLETS AND TUBERCULOSIS DRUG TARGETS
Zhang, Y. (2005) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.45.120403.100120 · Cited by 432
Metadata
- Authors
- Baulard, A. R., Betts, J. C., Engohang-Ndong, J., Quan, S., McAdam, R. A., Brennan, P. J., Locht, C., & Besra, G. S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-09
- Volume
- 275
- Issue
- 36
- Pages
- 28326-28331
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1981198757
- Cited by
- 311
- References
- 27
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Baulard, A. R., Betts, J. C., Engohang-Ndong, J., Quan, S., McAdam, R. A., Brennan, P. J., Locht, C., & Besra, G. S. (2000). Activation of the Pro-drug Ethionamide Is Regulated in Mycobacteria. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m003744200
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