HTH-type transcriptional regulator EthR (EthR)

HTH-type transcriptional regulator EthR (EthR) is a member of the TetR family of transcriptional repressors found in Mycobacterium tuberculosis [5, 10]. Its primary biological function is to negatively regulate the expression of the ethA gene, which encodes a flavin-containing monooxygenase [5, 9]. This enzyme, EthA, is essential for the bioactivation of the second-line antitubercular prodrug ethionamide into its active form [12, 14]. By repressing ethA, EthR limits the amount of active drug produced, contributing to the pathogen's natural resistance to ethionamide [7, 9]. In the context of drug development, EthR is a validated therapeutic target for boosting the efficacy of ethionamide, particularly in treating multidrug-resistant tuberculosis (MDR-TB) [1, 13]. Small-molecule inhibitors of EthR bind to its allosteric pocket, inducing a conformational change that abolishes its DNA-binding ability [5, 7]. This derepression leads to an overproduction of EthA, significantly enhancing the bioactivation of ethionamide and increasing its potency [3, 14]. This booster strategy allows for a reduction in the therapeutic dose of ethionamide, potentially mitigating its severe dose-dependent side effects and improving patient compliance [3, 6].

Other names

etaRRv3855EthR protein

EthR inhibitors bind to the repressor, inducing a conformational change that prevents DNA binding [5, 7]. This derepresses the ethA gene, leading to increased expression of EthA monooxygenase, which bioactivates the prodrug ethionamide into its active form [1, 14].