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

TitleStructural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2.
Publication TypeJournal Article
Year of Publication2017
AuthorsWohlkonig, A., H. Remaut, M. Moune, A. Tanina, F. Meyer, M. Desroses, J. Steyaert, N. Willand, A. R. Baulard, and R. Wintjens
JournalBiochem Biophys Res Commun
Volume487
Issue2
Pagination403-408
Date Published2017 05 27
ISSN1090-2104
KeywordsAntitubercular 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
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.

DOI10.1016/j.bbrc.2017.04.074
Alternate JournalBiochem. Biophys. Res. Commun.
PubMed ID28416386
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