|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|
|Date Published||2017 05 27|
|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|
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.
|Alternate Journal||Biochem. Biophys. Res. Commun.|
Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2.