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Trefzer C.,More Medicines for Tuberculosis MM4TB Consortium | Trefzer C.,Ecole Polytechnique Federale de Lausanne | Skovierova H.,More Medicines for Tuberculosis MM4TB Consortium | Skovierova H.,Comenius University | And 22 more authors.
Journal of the American Chemical Society | Year: 2012

Benzothiazinones (BTZs) are antituberculosis drug candidates with nanomolar bactericidal activity against tubercle bacilli. Here we demonstrate that BTZs are suicide substrates of the FAD-dependent decaprenylphosphoryl-β-d- ribofuranose 2′oxidase DprE1, an enzyme involved in cell-wall biogenesis. BTZs are reduced by DprE1 to an electrophile, which then reacts in a near-quantitative manner with an active-site cysteine of DprE1, thus providing a rationale for the extraordinary potency of BTZs. Mutant DprE1 enzymes from BTZ-resistant strains reduce BTZs to inert metabolites while avoiding covalent inactivation. Our results explain the basis for drug sensitivity and resistance to an exceptionally potent class of antituberculosis agents. © 2011 American Chemical Society.

Makarov V.,More Medicines for Tuberculosis MM4TB Consortium | Makarov V.,Russian Academy of Sciences | Lechartier B.,More Medicines for Tuberculosis MM4TB Consortium | Lechartier B.,Ecole Polytechnique Federale de Lausanne | And 23 more authors.
EMBO Molecular Medicine | Year: 2014

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.

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