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Towards a new combination therapy for tuberculosis with next generation benzothiazinones
Open accessAbstract
The benzothiazinone lead compound, BTZ043, kills Mycobacterium tuberculosis by inhibiting the essential flavo-enzyme DprE1, decaprenylphosphoryl-beta-D-ribose 2-epimerase. Here, we synthesized a new series of piperazine-containing benzothiazinones (PBTZ) and show that, like BTZ043, the preclinical candidate PBTZ169 binds covalently to DprE1. The crystal structure of the DprE1-PBTZ169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Compared to BTZ043, PBTZ169 has improved potency, safety and efficacy in zebrafish and mouse models of tuberculosis (TB). When combined with other TB drugs, PBTZ169 showed additive activity against M. tuberculosis in vitro except with bedaquiline (BDQ) where synergy was observed. A new regimen comprising PBTZ169, BDQ and pyrazinamide was found to be more efficacious than the standard three drug treatment in a murine model of chronic disease. PBTZ169 is thus an attractive drug candidate to treat TB in humans.
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A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis
Andries, K., Verhasselt, P., Guillemont, J., Göhlmann, H. W. H., Neefs, J.-M., Winkler, H., Van Gestel, J., Timmerman, P., Zhu, M., Lee, E., et al. (2005) · Science · doi:10.1126/science.1106753 · Cited by 2,191 · cited 16×
“As can be seen in Fig 9, the combination of PBTZ169 and BDQ was more effective than the standard treatment in reducing the number of CFU in both organs after 1 month of treatment ( P values = 0.004 for the lung, 0.002 for the spleen) whereas the addition of PZA did not further improve the potency of the combination at…”
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Cited by
Hartkoorn, R. C., Uplekar, S., & Cole, S. T. (2014) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00037-14 · Cited by 489
Self-citationNew agents for the treatment of drug-resistant Mycobacterium tuberculosis
Hoagland, D. T., Liu, J., Lee, R. B., & Lee, R. E. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.04.026 · Cited by 328
Antibiotics in the clinical pipeline in October 2019
Butler, M. S., & Paterson, D. L. (2020) · The Journal of Antibiotics · doi:10.1038/s41429-020-0291-8 · Cited by 264
Lansoprazole is an antituberculous prodrug targeting cytochrome bc1
Rybniker, J., Vocat, A., Sala, C., Busso, P., Pojer, F., Benjak, A., & Cole, S. T. (2015) · Nature Communications · doi:10.1038/ncomms8659 · Cited by 191
Self-citationAnimal Models of Tuberculosis: Zebrafish
van Leeuwen, L. M., van der Sar, A. M., & Bitter, W. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a018580 · Cited by 53
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Metadata
- Authors
- Makarov, V., Lechartier, B., Zhang, M., Neres, J., van der Sar, A. M., Raadsen, S. A., Hartkoorn, R. C., Ryabova, O. B., Vocat, A., Decosterd, L. A., Widmer, N., Buclin, T., Bitter, W., Andries, K., Pojer, F., Dyson, P. J., & Cole, S. T.
- Venue
- EMBO Molecular Medicine
- Published
- 2014-02-05
- Volume
- 6
- Issue
- 3
- Pages
- 372-383
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- OpenAlex
- W2126989272
- Cited by
- 380
- References
- 1
- FWCI
- 20.33
- Type
- journal article
- Language
- en
- Open access
- gold
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- Makarov, V., Lechartier, B., Zhang, M., Neres, J., van der Sar, A. M., Raadsen, S. A., Hartkoorn, R. C., Ryabova, O. B., Vocat, A., Decosterd, L. A., Widmer, N., Buclin, T., Bitter, W., Andries, K., Pojer, F., Dyson, P. J., & Cole, S. T. (2014). Towards a new combination therapy for tuberculosis with next generation benzothiazinones. EMBO Molecular Medicine. https://doi.org/10.1002/emmm.201303575
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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