The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

  • Antimicrob Agents Chemother. 2015 Aug;59(8):4446-52. doi: 10.1128/AAC.00778-15.
Vadim Makarov  1 ,  João Neres  2 ,  Ruben C Hartkoorn  2 ,  Olga B Ryabova  1 ,  Elena Kazakova  1 ,  Michal Šarkan  3 ,  Stanislav Huszár  3 ,  Jérémie Piton  2 ,  Gaëlle S Kolly  2 ,  Anthony Vocat  2 ,  Trent M Conroy  2 ,  Katarína Mikušová  3 ,  Stewart T Cole  4
Affiliations
  • 1. More Medicines for Tuberculosis Consortium‡ A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia.
  • 2. More Medicines for Tuberculosis Consortium‡ Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • 3. More Medicines for Tuberculosis Consortium‡ Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia.
  • 4. More Medicines for Tuberculosis Consortium‡ Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland [email protected].
PMID: 25987616 DOI: 10.1128/AAC.00778-15
Abstract

8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1) and display nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity. Here, we report the synthesis and characterization of the pyrrole-benzothiazinones PyrBTZ01 and PyrBTZ02, non-nitro-benzothiazinones that retain significant antimycobacterial activity, with MICs of 0.16 μg/ml against M. tuberculosis. These compounds inhibit DprE1 with 50% inhibitory concentration (IC50) values of <8 μM and present favorable in vitro absorption-distribution-metabolism-excretion/toxicity (ADME/T) and in vivo pharmacokinetic profiles. The most promising compound, PyrBTZ01, did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency.

Products