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New active leads for Tuberculosis booster drugs by structure-based drug discovery

Tatum, Natalie J; Liebeschuezt, John; Cole, Jason C.; Frita, Rosangela; Herledan, Adrien; Baulard, Alain; Willand, Nicolas; Pohl, Ehmke

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Authors

Natalie J Tatum

John Liebeschuezt

Jason C. Cole

Rosangela Frita

Adrien Herledan

Alain Baulard

Nicolas Willand



Abstract

The transcriptional regulator EthR from Mycobacterium tuberculosis, a member of the TetR family of prokaryotic homo-dimeric transcriptions factors, controls the expression of the mycobacterial mono-oxygenase EthA. Due to the fact that EthA is responsible for the bio-activation of the second-line tuberculosis pro-drug ethionamide, EthR inhibitors have been shown to boost drug efficacy by increasing EthA levels. Here, we present a comprehensive in-silico structure-based screening protocol that led to the identification of a number of novel scaffolds of EthR inhibitors. We present biophysical characterization of 85 potential leads, 20 of which showed binding by thermal shift assays. The co-crystal structures of EthR with four new ligands at resolution ranging from 2.1 to 1.4 Å confirm the binding and inactivation mode. The crystal structures include ligands with three new chemical scaffolds that will enable future lead development. Five of the lead compounds showed the desired booster effect with the most promising displaying an EC50 value of 0.76 μM.

Citation

Tatum, N. J., Liebeschuezt, J., Cole, J. C., Frita, R., Herledan, A., Baulard, A., …Pohl, E. (2017). New active leads for Tuberculosis booster drugs by structure-based drug discovery. Organic and Biomolecular Chemistry, 15(48), 10245-10255. https://doi.org/10.1039/c7ob00910k

Journal Article Type Article
Acceptance Date Nov 1, 2017
Online Publication Date Nov 1, 2017
Publication Date Nov 1, 2017
Deposit Date Nov 9, 2017
Publicly Available Date Mar 28, 2024
Journal Organic and Biomolecular Chemistry
Print ISSN 1477-0520
Electronic ISSN 1477-0539
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
Volume 15
Issue 48
Pages 10245-10255
DOI https://doi.org/10.1039/c7ob00910k