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

Lookup NU author(s): Dr Natalie TatumORCiD

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Royal Society of Chemistry, 2017.

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Abstract

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.

Publication metadata

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

Year: 2017

Volume: 15

Issue: 48

Pages: 10245-10255

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

URL: https://doi.org/10.1039/C7OB00910K

DOI: 10.1039/C7OB00910K

PubMed id: 29182187

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