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ACS Chem Biol. 2017 May 19;12(5):1390-1396. doi: 10.1021/acschembio.7b00091. Epub 2017 Apr 5.

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

Author information

1
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
2
Department of Biochemistry, University of Cambridge , 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
3
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
4
CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, Université de Lille , F-59000 Lille, France.
5
Institute for Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town 7935, South Africa.

Abstract

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.

PMID:
28314097
PMCID:
PMC5474694
DOI:
10.1021/acschembio.7b00091
[Indexed for MEDLINE]
Free PMC Article

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