Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell Mycobacterium tuberculosis Assays

Small-molecule inhibitors of the myco­bacterial transcriptional repressor EthR have previously been shown to act as boosters of the second-line anti­tuberculosis drug ethion­amide. Fragment-based drug discovery approaches have been used in the past to make highly potent EthR inhibitors with ethion­a...

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Published in:ACS chemical biology 2017-05, Vol.12 (5), p.1390-1396
Main Authors: Nikiforov, Petar O, Blaszczyk, Michal, Surade, Sachin, Boshoff, Helena I, Sajid, Andaleeb, Delorme, Vincent, Deboosere, Nathalie, Brodin, Priscille, Baulard, Alain R, Blundell, Tom L, Abell, Chris
Format: Article
Language:English
Subjects:
Antitubercular Agents
Bacterial Proteins
Drug Discovery
Drug Synergism
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Ethionamide - pharmacology
Ethionamide - therapeutic use
Ligands
Microbial Sensitivity Tests
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - enzymology
Repressor Proteins - antagonists & inhibitors
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Summary:Small-molecule inhibitors of the myco­bacterial transcriptional repressor EthR have previously been shown to act as boosters of the second-line anti­tuberculosis drug ethion­amide. Fragment-based drug discovery approaches have been used in the past to make highly potent EthR inhibitors with ethion­amide boosting activity both in vitro and ex vivo. Herein, we report the development of fragment-sized EthR ligands with nanomolar minimum effective concentration values for boosting the ethion­amide activity in Mycobacterium tuberculosis whole-cell assays.
ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.7b00091