Towards a new combination therapy for tuberculosis with next generation benzothiazinones.

Details

Serval ID
serval:BIB_5E4A334B83C9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Towards a new combination therapy for tuberculosis with next generation benzothiazinones.
Journal
Embo Molecular Medicine
Author(s)
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.
ISSN
1757-4684 (Electronic)
ISSN-L
1757-4676
Publication state
Published
Issued date
2014
Peer-reviewed
Oui
Volume
6
Number
3
Pages
372-383
Language
english
Notes
Publication types: Journal Article Publication Status: ppublish
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.
Pubmed
Web of science
Open Access
Yes
Create date
06/04/2014 15:33
Last modification date
20/10/2020 8:19
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