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

Journal Contribution - Journal Article

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.

Journal: Biochemical and Biophysical Research Communications
ISSN: 0006-291X
Issue: 2
Volume: 487
Pages: 403-408
Number of pages: 6
Publication year: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