• Alexandre Wohlkönig, Han Remaut, Martin Moune, Abdalkarim Tanina, Franck Meyer, Matthieu Desroses, Jan Steyaert, Nicolas Willand, Alain R Baulard, and René Wintjens.
• Center 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.
• Biochem. Biophys. Res. Commun. 2017 May 27; 487 (2): 403-408.

AbstractInhibition 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.Copyright © 2017 Elsevier Inc. All rights reserved.

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