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Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell $\textit{Mycobacterium tuberculosis}$ Assays

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Nikiforov, PO 
Blaszczyk, M 
Surade, S 
Boshoff, HI 
Sajid, A 


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.



Antitubercular Agents, Bacterial Proteins, Drug Discovery, Drug Synergism, Enzyme Inhibitors, Ethionamide, Ligands, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Repressor Proteins

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ACS Chemical Biology

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American Chemical Society
European Commission (260872)
Bill & Melinda Gates Foundation (via Foundation for the National Institutes of Health (FNIH)) (ABELL11HTB0)
Engineering and Physical Sciences Research Council (EP/K039520/1)
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.