Fragment-Based Optimized EthR Inhibitors with <i>in Vivo</i> Ethionamide Boosting Activity

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 <i>Mycobacterium tuberculosis</i> 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 <i>in vitro</i> 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 <i>in vitro</i> evaluation of the compounds, we identified a new oxadiazole compound as the first fragment-based ethionamide booster which proved to be active <i>in vivo</i>, in an acute model of tuberculosis infection.