Towards a new combination therapy for tuberculosis with next generation benzothiazinones
- 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., and Cole, S.T.
- ID
- ZDB-PUB-140415-17
- Date
- 2014
- Source
- EMBO Molecular Medicine 6(3): 372-383 (Journal)
- Registered Authors
- Bitter, Wilbert, van der Sar, Astrid M.
- Keywords
- none
- MeSH Terms
-
- Alcohol Oxidoreductases/chemistry
- Alcohol Oxidoreductases/metabolism
- Animals
- Antitubercular Agents/chemical synthesis
- Antitubercular Agents/pharmacology
- Antitubercular Agents/therapeutic use*
- Bacterial Proteins/chemistry
- Bacterial Proteins/metabolism
- Binding Sites
- Catalytic Domain
- Crystallography, X-Ray
- Disease Models, Animal
- Embryo, Nonmammalian/drug effects
- Hep G2 Cells
- Humans
- Lung/metabolism
- Mice
- Molecular Dynamics Simulation
- Mycobacterium tuberculosis/drug effects
- Piperazines/chemistry
- Piperazines/pharmacology
- Piperazines/therapeutic use
- Spiro Compounds/chemistry
- Spiro Compounds/pharmacokinetics
- Spiro Compounds/pharmacology
- Spiro Compounds/therapeutic use*
- Spleen/metabolism
- Thiazines/chemistry
- Thiazines/pharmacokinetics
- Thiazines/pharmacology
- Thiazines/therapeutic use*
- Tuberculosis/drug therapy*
- Zebrafish/growth & development
- PubMed
- 24500695 Full text @ EMBO Mol. Med.
The benzothiazinone lead compound, BTZ043, kills Mycobacterium tuberculosis by inhibiting the essential flavoenzyme DprE1, decaprenylphosphorylbetaDribose 2epimerase. Here, we synthesized a new series of piperazinecontaining benzothiazinones (PBTZ) and show that, like BTZ043, the preclinical candidate PBTZ169 binds covalently to DprE1. The crystal structure of the DprE1PBTZ169 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.