Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell $\textit{Mycobacterium tuberculosis}$ Assays
Authors
Nikiforov, Petar
Blaszczyk, Michal
Surade, S
Boshoff, HI
Sajid, A
Delorme, V
Deboosere, N
Brodin, P
Baulard, AR
Barry, CE
Publication Date
2017-05-19Journal Title
ACS Chemical Biology
ISSN
1554-8929
Publisher
American Chemical Society
Volume
12
Issue
5
Pages
1390-1396
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Nikiforov, P., Blaszczyk, M., Surade, S., Boshoff, H., Sajid, A., Delorme, V., Deboosere, N., et al. (2017). Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell $\textit{Mycobacterium tuberculosis}$ Assays. ACS Chemical Biology, 12 (5), 1390-1396. https://doi.org/10.1021/acschembio.7b00091
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 $\textit{in vitro}$ and $\textit{ex vivo}$. Herein, we report the development of fragment-sized EthR ligands with nanomolar minimum effective concentration values for boosting the ethionamide activity in $\textit{Mycobacterium tuberculosis}$ whole-cell assays.
Sponsorship
We would like to thank A. Coyne for help in the preparation of this manuscript. P.O.N. would like to thank the EPSRC for providing Ph.D. funding. We also thank the Bill and Melinda Gates Foundation and the EU FP7MM4TB Grant No. 260872, the ERC-STG INTRACELLTB Grant No. 260901, the Agence Nationale de la Recherche (ANR-10-EQPX-04-01), the Feder (12001407 (D-AL) Equipex Imaginex BioMed), the Intramural Research Program of the National Institutes of Health/NIAID, and the Région Nord Pas de Calais, France, for providing funding to support this work.
Funder references
EC FP7 CP (260872)
Bill & Melinda Gates Foundation (via Foundation for the National Institutes of Health (FNIH)) (ABELL11HTB0)
EPSRC (EP/K039520/1)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1021/acschembio.7b00091
This record's URL: https://www.repository.cam.ac.uk/handle/1810/264980
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International