Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2

Alexandre Wohlkönig; Han Remaut; Martin Moune; Abdalkarim Tanina; Franck Meyer; Matthieu Desroses; Jan Steyaert; Nicolas Willand; Alain R Baulard; René Wintjens

doi:10.1016/j.bbrc.2017.04.074

Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2

Alexandre Wohlkönig, Han Remaut, Martin Moune, Abdalkarim Tanina, Franck Meyer, Matthieu Desroses, Jan Steyaert, Nicolas Willand, Alain R Baulard, René Wintjens

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

Inhibition of transcriptional regulators of bacterial pathogens with the aim of reprogramming their metabolism to modify their antibiotic susceptibility constitutes a promising therapeutic strategy. One example is the bio-activation of the anti-tubercular pro-drug ethionamide, which activity could be enhanced by inhibiting the transcriptional repressor EthR. Recently, we discovered that inhibition of a second transcriptional repressor, EthR2, leads to the awakening of a new ethionamide bio-activation pathway. The x-ray structure of EthR2 was solved at 2.3 Å resolution in complex with a compound called SMARt-420 (Small Molecule Aborting Resistance). Detailed comparison and structural analysis revealed interesting insights for the upcoming structure-based design of EthR2 inhibitors as an alternative to revert ethionamide resistance in Mycobacterium tuberculosis.

Original language	English
Pages (from-to)	403-408
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	487
Issue number	2
DOIs	https://doi.org/10.1016/j.bbrc.2017.04.074
Publication status	Published - 27 May 2017

Keywords

Crystal structure
Drug design
Ethionamide
Ligand-binding interaction
TetR family
Transcriptional repressor
Models, Chemical
Isoxazoles/chemistry
Structure-Activity Relationship
Protein Interaction Mapping
Mycobacterium tuberculosis/metabolism
Spiro Compounds/chemistry
Repressor Proteins/chemistry
Antitubercular Agents/chemistry
Protein Binding
Protein Conformation
Bacterial Proteins/chemistry
Molecular Docking Simulation
Binding Sites

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10.1016/j.bbrc.2017.04.074

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Wohlkönig, A., Remaut, H., Moune, M., Tanina, A., Meyer, F., Desroses, M., Steyaert, J., Willand, N., Baulard, A. R., & Wintjens, R. (2017). Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2. Biochemical and Biophysical Research Communications, 487(2), 403-408. https://doi.org/10.1016/j.bbrc.2017.04.074

Wohlkönig, Alexandre ; Remaut, Han ; Moune, Martin ; Tanina, Abdalkarim ; Meyer, Franck ; Desroses, Matthieu ; Steyaert, Jan ; Willand, Nicolas ; Baulard, Alain R ; Wintjens, René. / Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2. In: Biochemical and Biophysical Research Communications. 2017 ; Vol. 487, No. 2. pp. 403-408.

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title = "Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2",

abstract = "Inhibition of transcriptional regulators of bacterial pathogens with the aim of reprogramming their metabolism to modify their antibiotic susceptibility constitutes a promising therapeutic strategy. One example is the bio-activation of the anti-tubercular pro-drug ethionamide, which activity could be enhanced by inhibiting the transcriptional repressor EthR. Recently, we discovered that inhibition of a second transcriptional repressor, EthR2, leads to the awakening of a new ethionamide bio-activation pathway. The x-ray structure of EthR2 was solved at 2.3 {\AA} resolution in complex with a compound called SMARt-420 (Small Molecule Aborting Resistance). Detailed comparison and structural analysis revealed interesting insights for the upcoming structure-based design of EthR2 inhibitors as an alternative to revert ethionamide resistance in Mycobacterium tuberculosis.",

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author = "Alexandre Wohlk{\"o}nig and Han Remaut and Martin Moune and Abdalkarim Tanina and Franck Meyer and Matthieu Desroses and Jan Steyaert and Nicolas Willand and Baulard, {Alain R} and Ren{\'e} Wintjens",

year = "2017",

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day = "27",

doi = "10.1016/j.bbrc.2017.04.074",

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Wohlkönig, A , Remaut, H, Moune, M, Tanina, A, Meyer, F, Desroses, M, Steyaert, J, Willand, N, Baulard, AR & Wintjens, R 2017, 'Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2', Biochemical and Biophysical Research Communications, vol. 487, no. 2, pp. 403-408. https://doi.org/10.1016/j.bbrc.2017.04.074

Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2. / Wohlkönig, Alexandre ; Remaut, Han; Moune, Martin; Tanina, Abdalkarim; Meyer, Franck; Desroses, Matthieu; Steyaert, Jan; Willand, Nicolas; Baulard, Alain R; Wintjens, René.

In: Biochemical and Biophysical Research Communications, Vol. 487, No. 2, 27.05.2017, p. 403-408.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2

AU - Wohlkönig, Alexandre

AU - Remaut, Han

AU - Moune, Martin

AU - Tanina, Abdalkarim

AU - Meyer, Franck

AU - Desroses, Matthieu

AU - Steyaert, Jan

AU - Willand, Nicolas

AU - Baulard, Alain R

AU - Wintjens, René

PY - 2017/5/27

Y1 - 2017/5/27

N2 - Inhibition of transcriptional regulators of bacterial pathogens with the aim of reprogramming their metabolism to modify their antibiotic susceptibility constitutes a promising therapeutic strategy. One example is the bio-activation of the anti-tubercular pro-drug ethionamide, which activity could be enhanced by inhibiting the transcriptional repressor EthR. Recently, we discovered that inhibition of a second transcriptional repressor, EthR2, leads to the awakening of a new ethionamide bio-activation pathway. The x-ray structure of EthR2 was solved at 2.3 Å resolution in complex with a compound called SMARt-420 (Small Molecule Aborting Resistance). Detailed comparison and structural analysis revealed interesting insights for the upcoming structure-based design of EthR2 inhibitors as an alternative to revert ethionamide resistance in Mycobacterium tuberculosis.

AB - Inhibition of transcriptional regulators of bacterial pathogens with the aim of reprogramming their metabolism to modify their antibiotic susceptibility constitutes a promising therapeutic strategy. One example is the bio-activation of the anti-tubercular pro-drug ethionamide, which activity could be enhanced by inhibiting the transcriptional repressor EthR. Recently, we discovered that inhibition of a second transcriptional repressor, EthR2, leads to the awakening of a new ethionamide bio-activation pathway. The x-ray structure of EthR2 was solved at 2.3 Å resolution in complex with a compound called SMARt-420 (Small Molecule Aborting Resistance). Detailed comparison and structural analysis revealed interesting insights for the upcoming structure-based design of EthR2 inhibitors as an alternative to revert ethionamide resistance in Mycobacterium tuberculosis.

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KW - Drug design

KW - Ethionamide

KW - Ligand-binding interaction

KW - TetR family

KW - Transcriptional repressor

KW - Models, Chemical

KW - Isoxazoles/chemistry

KW - Structure-Activity Relationship

KW - Protein Interaction Mapping

KW - Mycobacterium tuberculosis/metabolism

KW - Spiro Compounds/chemistry

KW - Repressor Proteins/chemistry

KW - Antitubercular Agents/chemistry

KW - Protein Binding

KW - Protein Conformation

KW - Bacterial Proteins/chemistry

KW - Molecular Docking Simulation

KW - Binding Sites

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U2 - 10.1016/j.bbrc.2017.04.074

DO - 10.1016/j.bbrc.2017.04.074

M3 - Article

C2 - 28416386

VL - 487

SP - 403

EP - 408

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 2

ER -

Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2

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Keywords

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