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Updated: Aug 2, 2026

System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
Published on: April 5, 2017
Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis
Alexandre Wohlkönig1, Han Remaut1, Martin Moune2
1Center for Structural Biology, Vlaams Instituut voor Biotechnology (VIB), Pleinlaan 2, B-1050 Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Pleinlaan 2, B-1050 Brussels, Belgium.
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.
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