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Experimental Therapeutics

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

Vadim Makarov, João Neres, Ruben C. Hartkoorn, Olga B. Ryabova, Elena Kazakova, Michal Šarkan, Stanislav Huszár, Jérémie Piton, Gaëlle S. Kolly, Anthony Vocat, Trent M. Conroy, Katarína Mikušová, Stewart T. Cole
Vadim Makarov
aMore Medicines for Tuberculosis Consortium‡
bA. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia
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João Neres
aMore Medicines for Tuberculosis Consortium‡
cGlobal Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Ruben C. Hartkoorn
aMore Medicines for Tuberculosis Consortium‡
cGlobal Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Olga B. Ryabova
aMore Medicines for Tuberculosis Consortium‡
bA. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia
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Elena Kazakova
aMore Medicines for Tuberculosis Consortium‡
bA. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia
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Michal Šarkan
aMore Medicines for Tuberculosis Consortium‡
dDepartment of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia
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Stanislav Huszár
aMore Medicines for Tuberculosis Consortium‡
dDepartment of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia
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Jérémie Piton
aMore Medicines for Tuberculosis Consortium‡
cGlobal Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Gaëlle S. Kolly
aMore Medicines for Tuberculosis Consortium‡
cGlobal Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Anthony Vocat
aMore Medicines for Tuberculosis Consortium‡
cGlobal Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Trent M. Conroy
aMore Medicines for Tuberculosis Consortium‡
cGlobal Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Katarína Mikušová
aMore Medicines for Tuberculosis Consortium‡
dDepartment of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia
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Stewart T. Cole
aMore Medicines for Tuberculosis Consortium‡
cGlobal Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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DOI: 10.1128/AAC.00778-15
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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.

FOOTNOTES

    • Received 2 April 2015.
    • Returned for modification 28 April 2015.
    • Accepted 7 May 2015.
    • Accepted manuscript posted online 18 May 2015.
  • ‡ For this virtual institution, see http://www.mm4tb.org.

  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.00778-15.

  • Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis
Vadim Makarov, João Neres, Ruben C. Hartkoorn, Olga B. Ryabova, Elena Kazakova, Michal Šarkan, Stanislav Huszár, Jérémie Piton, Gaëlle S. Kolly, Anthony Vocat, Trent M. Conroy, Katarína Mikušová, Stewart T. Cole
Antimicrobial Agents and Chemotherapy Jul 2015, 59 (8) 4446-4452; DOI: 10.1128/AAC.00778-15

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The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis
Vadim Makarov, João Neres, Ruben C. Hartkoorn, Olga B. Ryabova, Elena Kazakova, Michal Šarkan, Stanislav Huszár, Jérémie Piton, Gaëlle S. Kolly, Anthony Vocat, Trent M. Conroy, Katarína Mikušová, Stewart T. Cole
Antimicrobial Agents and Chemotherapy Jul 2015, 59 (8) 4446-4452; DOI: 10.1128/AAC.00778-15
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