TY - JOUR
T1 - Towards a new combination therapy for tuberculosis with next generation benzothiazinones
AU - Makarov, V.
AU - Lechartier, B.
AU - Zhang, M.
AU - Neres, J.
AU - van der Sar, A.M.
AU - Raadsen, S.A.
AU - Hartkoorn, R.C.
AU - Ryabova, O.B.
AU - Vocat, A.
AU - Decosterd, L.A.
AU - Widmer, N.
AU - Buclin, T.
AU - Bitter, W.
AU - Andries, K.
AU - Pojer, F.
AU - Dyson, P.J.
AU - Cole, S.T.
N1 - 1757-4684 Makarov, Vadim Lechartier, Benoit Zhang, Ming Neres, Joao van der 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 Journal Article England EMBO Mol Med. 2014 Mar 1;6(3):372-83. doi: 10.1002/emmm.201303575. Epub 2014 Feb 5.
PY - 2014
Y1 - 2014
N2 - 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. © 2014 The Authors.
AB - 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. © 2014 The Authors.
U2 - https://doi.org/10.1002/emmm.201303575
DO - https://doi.org/10.1002/emmm.201303575
M3 - Article
C2 - 24500695
SN - 1757-4676
VL - 6
SP - 372
EP - 383
JO - Embo Molecular Medicine
JF - Embo Molecular Medicine
IS - 3
ER -
