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

• Published in: Biochemical and biophysical research communications Vol. 487; no. 2; pp. 403 - 408
• Main Authors: Wohlkönig, Alexandre, Remaut, Han, Moune, Martin, Tanina, Abdalkarim, Meyer, Franck, Desroses, Matthieu, Steyaert, Jan, Willand, Nicolas, Baulard, Alain R., Wintjens, René
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.05.2017
• Subjects: Antitubercular Agents - chemistry; Bacterial Proteins - chemistry; Bacterial Proteins - ultrastructure; Binding Sites; Crystal structure; Drug design; Ethionamide; Isoxazoles - chemistry; Ligand-binding interaction; Medicin och hälsovetenskap; Models, Chemical; Molecular Docking Simulation; Mycobacterium tuberculosis - metabolism; Protein Binding; Protein Conformation; Protein Interaction Mapping; Repressor Proteins - chemistry; Repressor Proteins - ultrastructure; Spiro Compounds - chemistry; Structure-Activity Relationship; TetR family; Transcriptional repressor; Ethionamide; Drug design; TetR family; Ligand-binding interaction; Transcriptional repressor; Crystal structure
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2017.04.074

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. [Display omitted] •The structure of the newly discovered M. tuberculosis target EthR2 was solved.•EthR2 bound to SMARt-420 was determined at 2.3 Å resolution.•Ligand-binding features of EthR2 are revealed.•EthR and EthR2 binding pockets are compared.