Fragment-Based Optimized EthR Inhibitors with <i>in Vivo</i> Ethionamide Boosting Activity
Baptiste Villemagne, Arnaud Machelart, Ngoc Chau Tran, Marion Flipo, Martin Moune, Florence Leroux, Catherine Piveteau, Alexandre Wohlkönig, René Wintjens, Xue Li, Ruxandra Gref, Priscille Brodin, Benoît Déprez, Alain R. Baulard, Nicolas Willand
Abstract
Killing more than one million people each year, tuberculosis remains the leading cause of death from a single infectious agent. The growing threat of multidrug-resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. EthR, a mycobacterial transcriptional regulator, is involved in the control of the bioactivation of the second-line drug ethionamide. We have previously reported the discovery of in vitro nanomolar boosters of ethionamide through fragment-based approaches. In this study, we have further explored the structure–activity and structure–property relationships in this chemical family. By combining structure-based drug design and in vitro evaluation of the compounds, we identified a new oxadiazole compound as the first fragment-based ethionamide booster which proved to be active in vivo, in an acute model of tuberculosis infection.