The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis
Open accessAbstract
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 Mycobacterium tuberculosis (MTb) have allowed us to demonstrate that ETA is activated by S -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 [ 14 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.
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Cites
Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence
Cole, S. T., Brosch, R., Parkhill, J., Garnier, T., Churcher, C., Harris, D., Gordon, S. V., Eiglmeier, K., Gas, S., Barry, C. E., et al. (1998) · Nature · doi:10.1038/31159 · Cited by 7,847
Self-citationinhA , a Gene Encoding a Target for Isoniazid and Ethionamide in Mycobacterium tuberculosis
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The catalase—peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis
Zhang, Y., Heym, B., Allen, B., Young, D., & Cole, S. (1992) · Nature · doi:10.1038/358591a0 · Cited by 1,299
Cited by
Comprehensive identification of conditionally essential genes in mycobacteria
Sassetti, C. M., Boyd, D. H., & Rubin, E. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.231275498 · Cited by 616
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
Bacterial Fatty Acid Biosynthesis: Targets for Antibacterial Drug Discovery
Campbell, J. W., & Cronan, J. E. (2001) · Annual Review of Microbiology · doi:10.1146/annurev.micro.55.1.305 · Cited by 479
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
Altered NADH/NAD + Ratio Mediates Coresistance to Isoniazid and Ethionamide in Mycobacteria
Vilchèze, C., Weisbrod, T. R., Chen, B., Kremer, L., Hazbón, M. H., Wang, F., Alland, D., Sacchettini, J. C., & Jacobs, W. R. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.2.708-720.2005 · Cited by 284
Metadata
- Authors
- DeBarber, A. E., Mdluli, K., Bosman, M., Bekker, L.-G., & Barry, C. E.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2000-08-15
- Volume
- 97
- Issue
- 17
- Pages
- 9677-9682
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2164087631
- Cited by
- 338
- References
- 3
- FWCI
- 4.66
- Type
- journal article
- Language
- en
- Open access
- green
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- DeBarber, A. E., Mdluli, K., Bosman, M., Bekker, L.-G., & Barry, C. E. (2000). Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.97.17.9677
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