EthR transcriptional repressor (EthR)

EthR is a transcriptional repressor belonging to the TetR family, found in Mycobacterium tuberculosis. Its primary biological role is to negatively regulate the expression of the ethA gene, which encodes a flavin-containing monooxygenase responsible for the activation of the second-line antitubercular prodrug ethionamide (ETH). By binding to the operator region of the ethA promoter, EthR limits the production of EthA, thereby contributing to the low intrinsic sensitivity of M. tuberculosis to ethionamide and facilitating the emergence of drug resistance. In the context of drug development, EthR is a significant therapeutic target for 'booster' compounds. Small molecule inhibitors that bind to the EthR ligand-binding pocket induce a conformational change that prevents the protein from binding to DNA. This inhibition leads to the derepression and overexpression of EthA, significantly enhancing the bioactivation of ethionamide and effectively lowering the minimum inhibitory concentration (MIC) required to kill the bacteria. This strategy aims to improve the efficacy of ethionamide treatment while potentially reducing dose-related side effects in patients with tuberculosis.

Other names

HTH-type transcriptional repressor EthREthionamide resistance regulatorTetR-family transcriptional repressor EthR

Inhibition of EthR prevents its binding to the ethA promoter, leading to the overexpression of the EthA monooxygenase, which subsequently increases the bioactivation of the prodrug ethionamide into its active cytotoxic form.