Ethionamide resistance regulator (EthR) (EthR)

Ethionamide resistance regulator (EthR) is a transcriptional repressor in Mycobacterium tuberculosis that belongs to the TetR family of regulators (UniProt P9WMC1). It negatively regulates the expression of the ethA gene, which encodes a flavin-containing monooxygenase required to activate the prodrug ethionamide into its bactericidal form (PubMed: 12504015). By repressing ethA, EthR contributes to the intrinsic resistance of the bacteria to ethionamide treatment. Alpibectir (also known as BDM41906 or BVL-GSK098) is a small-molecule inhibitor that targets the hydrophobic cavity of EthR (PubMed: 33568654). Binding of alpibectir prevents EthR from interacting with the ethA promoter, thereby boosting the production of EthA and significantly enhancing the sensitivity of M. tuberculosis to ethionamide. This therapeutic approach aims to lower the effective dose of ethionamide, potentially reducing its dose-dependent toxicity while improving outcomes for patients with multi-drug resistant tuberculosis (BioVersys, 2023).

Other names

HTH-type transcriptional regulator EthRTranscriptional repressor EthREthR proteinEthR regulator

Inhibition of EthR binding to the ethA promoter, leading to upregulation of the EthA monooxygenase and increased activation of the prodrug ethionamide.