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 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

Cite this paper

@article{Wohlknig2017StructuralAO, title={Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2.}, 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 Alain R Baulard and Ren{\'e} Wintjens}, journal={Biochemical and biophysical research communications}, year={2017}, volume={487 2}, pages={403-408} }