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

Abstract

With more than 1.6 million deaths per year, tuberculosis (TB) is today the major cause of mortality resulting from a bacterial infection. The principal obstacles to the global control of this infectious disease include the difficulties to detect and cure a sufficient number of cases to interrupt transmission. In addition, multidrug-resistant-TB (MDR-TB) has emerged as a major concern worldwide. Therapeutic solutions to stem this scourge are based on a 2 to 4 year treatment regimen of less effective second-line drug cocktails, often associated with serious side effects, which reduces patients compliance and thus leads to high rates of recurrence and mortality. In parallel to the search for new targets and new class of antibiotics, the development of strategies to improve the efficacy of drugs already used in the clinic have been proposed. One of these strategies takes advantage of the fact that many first-line and second-line anti-tubercular drugs are pro-drugs. Indeed, they need to be bioactivated by drug-specific mycobacterial enzymes in order to develop their anti-bacterial activity. Thioamides (ethionamide or prothionamide) are among the most frequently used drugs for the treatment of drug-resistant tuberculosis. Bioactivation of ethionamide occurs through the catalysis of a flavin-dependent Baeyer-Villiger monooxygenase called EthA. The resulting NAD-adduct inhibits InhA, an enoyl-ACP reductase of the type II fatty acid synthase (FAS-II) system, involved in cell-wall synthesis. The transcriptional repressor EthR, in turn, tightly controls the expression of ethA. A new therapeutic concept emerged from this observation and the development of EthR inhibitors was proposed as a solution to improve ethioanmide activity. 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 compounds able to inhibit EthR and boost the bioactivation of ETH in vitro and in vivo. We finally discuss the limitations of this approach and the breakthroughs in the identification of new chemical series and alternative bioactivation pathways that paves the way for the clinical development of a combination allowing thioamides to return fully active against all sensitive or resistant clinical isolates.

In silico identification of novel chemical compounds with anti-TB potential for the inhibition of InhA and EthR from Mycobacterium tuberculosis

“…Both require the EthR respectively, leading to disrupting the MA biosynthesis pathway. [ADAPTED FROM: 26,28] formation of covalent adducts with NAD co-factor on oxidative activation to act on the InhA enzyme which is involved in mycolic acid synthesis. (Figure 2) [25,26,27].…”