Title | Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Wohlkonig, A., H. Remaut, M. Moune, A. Tanina, F. Meyer, M. Desroses, J. Steyaert, N. Willand, A. R. Baulard, and R. Wintjens |
Journal | Biochem Biophys Res Commun |
Volume | 487 |
Issue | 2 |
Pagination | 403-408 |
Date Published | 2017 05 27 |
ISSN | 1090-2104 |
Keywords | Antitubercular Agents, Bacterial Proteins, Binding Sites, Isoxazoles, Models, Chemical, Molecular Docking Simulation, Mycobacterium tuberculosis, Protein Binding, Protein Conformation, Protein Interaction Mapping, Repressor Proteins, Spiro Compounds, Structure-Activity Relationship |
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. |
DOI | 10.1016/j.bbrc.2017.04.074 |
Alternate Journal | Biochem. Biophys. Res. Commun. |
PubMed ID | 28416386 |
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