Open Access
Towards a new combination therapy for tuberculosis with next generation benzothiazinones
Vadim Makarov
1, 2
,
Benoit Lechartier
1, 3
,
Ming Zhang
1, 3
,
João Neres
1, 3
,
Astrid M. van der Sar
4
,
Susanne A Raadsen
4
,
Ruben C Hartkoorn
1, 3
,
Olga B. Ryabova
1, 2
,
Anthony Vocat
1, 3
,
Laurent A. Decosterd
5
,
Nicolas Widmer
5
,
Thierry Buclin
5
,
Wilbert Bitter
4, 6
,
Koen Andries
7
,
Florence Pojer
1, 3
,
Paul J Dyson
8
,
Stewart T Cole
1, 3
1
More Medicines for Tuberculosis (MM4TB) Consortium www.mm4tb.org
7
Janssen Infectious Diseases Beerse Belgium
|
Publication type: Journal Article
Publication date: 2014-02-05
scimago Q1
wos Q1
SJR: 3.571
CiteScore: 15.9
Impact factor: 8.3
ISSN: 17574676, 17574684
PubMed ID:
24500695
Molecular Medicine
Abstract
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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Total citations:
344
Citations from 2024:
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(14%)
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GOST
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Makarov V. et al. Towards a new combination therapy for tuberculosis with next generation benzothiazinones // EMBO Molecular Medicine. 2014. Vol. 6. No. 3. pp. 372-383.
GOST all authors (up to 50)
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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. Towards a new combination therapy for tuberculosis with next generation benzothiazinones // EMBO Molecular Medicine. 2014. Vol. 6. No. 3. pp. 372-383.
Cite this
RIS
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TY - JOUR
DO - 10.1002/emmm.201303575
UR - https://www.embopress.org/doi/10.1002/emmm.201303575
TI - Towards a new combination therapy for tuberculosis with next generation benzothiazinones
T2 - EMBO Molecular Medicine
AU - Makarov, Vadim
AU - Lechartier, Benoit
AU - Zhang, Ming
AU - Neres, João
AU - van der Sar, Astrid M.
AU - Raadsen, Susanne A
AU - Hartkoorn, Ruben C
AU - Ryabova, Olga B.
AU - Vocat, Anthony
AU - Decosterd, Laurent A.
AU - Widmer, Nicolas
AU - Buclin, Thierry
AU - Bitter, Wilbert
AU - Andries, Koen
AU - Pojer, Florence
AU - Dyson, Paul J
AU - Cole, Stewart T
PY - 2014
DA - 2014/02/05
PB - Springer Nature
SP - 372-383
IS - 3
VL - 6
PMID - 24500695
SN - 1757-4676
SN - 1757-4684
ER -
Cite this
BibTex (up to 50 authors)
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@article{2014_Makarov,
author = {Vadim Makarov and Benoit Lechartier and Ming Zhang and João Neres and Astrid M. van der Sar and Susanne A Raadsen and Ruben C Hartkoorn and Olga B. Ryabova and Anthony Vocat and Laurent A. Decosterd and Nicolas Widmer and Thierry Buclin and Wilbert Bitter and Koen Andries and Florence Pojer and Paul J Dyson and Stewart T Cole},
title = {Towards a new combination therapy for tuberculosis with next generation benzothiazinones},
journal = {EMBO Molecular Medicine},
year = {2014},
volume = {6},
publisher = {Springer Nature},
month = {feb},
url = {https://www.embopress.org/doi/10.1002/emmm.201303575},
number = {3},
pages = {372--383},
doi = {10.1002/emmm.201303575}
}
Cite this
MLA
Copy
Makarov, Vadim, et al. “Towards a new combination therapy for tuberculosis with next generation benzothiazinones.” EMBO Molecular Medicine, vol. 6, no. 3, Feb. 2014, pp. 372-383. https://www.embopress.org/doi/10.1002/emmm.201303575.
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