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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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  • FIG 1
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    FIG 1

    Structures of BTZ043, PBTZ169, and PyrBTZ derivatives and their respective MICs against M. tuberculosis H37Rv.

  • FIG 2
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    FIG 2

    Synthetic routes for the synthesis of pyrrole-BTZs. Step a, NaHS, NH4Cl, ethanol; step b, (i) 2,5-dimethoxytetrahydrofuran, acetic acid, reflux; (ii) NaOH; step c, 2,5-hexanedione, p-toluenesulfonic acid, toluene, reflux.

  • FIG 3
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    FIG 3

    Comparative inhibition of DPA synthesis. Decaprenylphosphoryl-β-d-ribose epimerization by M. tuberculosis H37Ra cells was inhibited by PyrBTZ01 (200 μg/ml), PyrBTZ02 (200 μg/ml), and BTZ043 (25 μg/ml). The ratios of the intensities of the DPA and DPR bands (quantified in ImageJ) are also shown.

  • FIG 4
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    FIG 4

    Molecular docking of pyrrole-BTZs in the DprE1 active site. Superposition of the M. tuberculosis DprE1 crystal structure with BTZ043 (A) or PBTZ169 (B) and the modeled structures of docked PyrBTZ01 (blue carbons) (C) and docked PyrBTZ02 (red carbons) (D) show an induced-fit complex. Cocrystallized DprE1 with PBTZ169 (PDB accession no. 4NCR) (yellow carbons) was used as the template. Residues important for the interactions are shown as sticks. FAD, flavin adenine dinucleotide.

  • FIG 5
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    FIG 5

    PK profiles in plasma following oral administration of PyrBTZ01 (50 mg/kg) or BTZ043 (25 mg/kg) to BALB/c mice. Data for BTZ043 in the plot were reported previously (3).

Tables

  • Figures
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  • TABLE 1

    MIC99 values for PyrBTZ01 and PyrBTZ02 against wild-type and BTZ-resistant mycobacterial strains

    StrainAmino acid at position 387MIC99 (μg/ml)
    PyrBTZ01PyrBTZ02BTZ043
    M. tuberculosis H37RvCys0.160.160.001
    M. tuberculosis NTB1Ser100>10010
    M. tuberculosis ss18bCys>100>100>10
    M. smegmatis mc2155Cysa0.780.390.004
    M. smegmatis MN47Glya>100>1004
    M. smegmatis MN84Sera>100>100>16
    M. bovis BCGCys0.390.20.003
    M. bovis BCG BN2Ser25>100>16
    • ↵a The active site cysteine in M. smegmatis DprE1 is Cys394.

  • TABLE 2

    IC50 values measured for PyrBTZ01, PyrBTZ02, and BTZ043 against wild-type and BTZ-resistant M. tuberculosis DprE1

    CompoundIC50 (μM)
    Wild-typeC387GC387S
    PyrBTZ011.6111.44.00
    PyrBTZ027.34>4027.7
    BTZ0430.004250.03950.0108
  • TABLE 3

    Cytotoxicity (TD50) and selectivity index values

    Cell linePyrBTZ01PyrBTZ02BTZ043
    TD50 (μg/ml)SITD50 (μg/ml)SITD50 (μg/ml)SI
    HepG247294945881919,000
    Huh750313815061616,000
    A54951319>100>6253434,000
    THP146288976067777,000
  • TABLE 4

    Metabolic stability of PyrBTZ01 and PyrBTZ02 in the presence of mouse and human microsomes

    CompoundCLint (μl/min/mg protein)
    Mouse microsomesHuman microsomes
    Carbamazepine2.100.60
    PyrBTZ0122.712.2
    PyrBTZ0216.222.3
    BTZ04316.54.20
    PBTZ16936.720.8

Additional Files

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    • Supplemental file 1 -

      Supplemental material describing the synthetic route for PyrBTZ.

      PDF, 209K

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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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