Transcriptional regulator EthR (EthR)

Transcriptional regulator EthR is a member of the TetR family of repressors in Mycobacterium tuberculosis that plays a critical role in regulating the bioactivation of the antitubercular prodrug ethionamide [1, 10]. It primarily functions by binding to the operator region of the ethA gene, thereby repressing the production of the EthA monooxygenase [1, 6]. EthA is the enzyme responsible for the bioactivation of the second-line antitubercular prodrug ethionamide into its active form [4, 6]. Consequently, EthR acts as a key regulator of ethionamide sensitivity; its inhibition leads to increased EthA levels and enhanced drug activation [2, 7]. This mechanism has made EthR a high-priority target for booster compounds designed to increase the therapeutic index of ethionamide [3, 6]. Small-molecule inhibitors of EthR, such as BDM31343, induce a conformational change that prevents DNA binding, effectively derepressing ethA [6, 9]. This strategy is particularly valuable in the context of multidrug-resistant tuberculosis (MDR-TB) to overcome resistance and reduce dose-related toxicity [2, 7]. Additionally, EthR activity is modulated by bacterial kinases such as PknF through phosphorylation, which negatively affects its DNA-binding affinity [8, 10].

Other names

HTH-type transcriptional regulator EthREthionamide resistance proteinRv3855TetR-family transcriptional regulator EthR

EthR inhibitors bind to the EthR repressor, inducing a conformational change that prevents it from binding to the operator of the ethA gene. This results in the upregulation of the monooxygenase EthA, which bioactivates the prodrug ethionamide into its active form, thereby increasing the drug's potency and allowing for lower therapeutic doses.