Open AccessTowards a new combination therapy for tuberculosis with next generation benzothiazinones
Author(s) -
Makarov Vadim,
Lechartier Benoit,
Zhang Ming,
Neres João,
Sar Astrid M,
Raadsen Susanne A,
Hartkoorn Ruben C,
Ryabova Olga B,
Vocat Anthony,
Decosterd Laurent A,
Widmer Nicolas,
Buclin Thierry,
Bitter Wilbert,
Andries Koen,
Pojer Florence,
Dyson Paul J,
Cole Stewart T
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201303575
Subject(s) - bedaquiline , pyrazinamide , tuberculosis , mycobacterium tuberculosis , pharmacology , potency , chemistry , medicine , drug , in vitro , biochemistry , pathology
The benzothiazinone lead compound, BTZ 043, 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 BTZ 043, the preclinical candidate PBTZ 169 binds covalently to DprE1. The crystal structure of the DprE1‐ PBTZ 169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Compared to BTZ 043, PBTZ 169 has improved potency, safety and efficacy in zebrafish and mouse models of tuberculosis ( TB ). When combined with other TB drugs, PBTZ 169 showed additive activity against M. tuberculosis in vitro except with bedaquiline ( BDQ ) where synergy was observed. A new regimen comprising PBTZ 169, BDQ and pyrazinamide was found to be more efficacious than the standard three drug treatment in a murine model of chronic disease. PBTZ 169 is thus an attractive drug candidate to treat TB in humans.