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Lookup NU author(s): Dr Natalie Tatum
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Royal Society of Chemistry, 2017.
For re-use rights please refer to the publisher's terms and conditions.
The transcriptional repressor EthR from Mycobacterium tuberculosis, a member of the TetR family of prokaryotic homo-dimeric transcription factors, controls the expression of the mycobacterial mono-oxygenase EthA. EthA is responsible for the bio-activation of the second-line tuberculosis pro-drug ethionamide, and consequently EthR inhibitors boost drug efficacy. Here, we present a comprehensive in silicostructure-based screening protocol that led to the identification of a number of novel scaffolds of EthR inhibitors in subsequent biophysical screening by thermal shift assay. Growth inhibition assays demonstrated that five of the twenty biophysical hits were capable of boosting ethionamide activity in vitro, with the best novel scaffold displaying an EC50 of 34 μM. In addition, 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, and will enable future lead development.
Author(s): Tatum NJ, Liebeschuetz JW, Cole JC, Frita R, Herledan A, Baulard AR, Willand N, Pohl, E
Publication type: Article
Publication status: Published
Journal: Organic and Biomolecular Chemistry
Print publication date: 01/12/2017
Online publication date: 01/11/2017
Acceptance date: 01/11/2017
Date deposited: 31/05/2018
ISSN (print): 1477-0520
ISSN (electronic): 1477-0539
Publisher: Royal Society of Chemistry
PubMed id: 29182187
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