Recent advances in the design of inhibitors of mycobacterial transcriptional regulators to boost thioamides anti-tubercular activity and circumvent acquired-resistance

Abstract Since few years, tuberculosis (TB) rivals AIDS as the leading cause of death worldwide. In addition, multidrug-resistant-TB (MDR-TB) has emerged as a major concern. Therapeutic solutions to stem this scourge are based on a 2–4 year treatment regimen of second-line drug cocktails, often associated with serious side effects, which does not facilitate patients compliance. In parallel to the search for new class of antibiotics, the development of alternative strategies to improve the efficacy of drugs already used in the clinic has been proposed. One of these strategies takes advantage of the fact that many anti-TB drugs are bioactivated by specific mycobacterial enzymes. Bioactivation of ethionamide or prothionamide, leading to inhibition of mycolic acids biosynthesis, involves a flavin-dependent Baeyer-Villiger monooxygenase called EthA, which expression is under the control of the transcriptional repressor EthR. A new therapeutic concept emerged from this observation and the development of EthR inhibitors was proposed as a solution to improve ethionamide efficacy. In this chapter, we outline the most recent efforts of different research groups, using modern drug discovery strategies that led to the design, discovery and optimization of the first inhibitors of EthR and boosters of ETH bioactivation in vitro and in vivo. We finally discuss the limitations of this approach and we highlight the breakthroughs in the identification of new chemical series and alternative bioactivation pathways. This discovery paves the way for the clinical development of a combination allowing thioamides to return fully active against all sensitive or resistant clinical isolates.