Ethionamide transcriptional repressor (EthR) (EthR)

Ethionamide transcriptional repressor (EthR) is a member of the TetR family of transcriptional regulators in Mycobacterium tuberculosis that plays a critical role in modulating drug sensitivity (UniProt: P9WMC1). Its primary biological function is to repress the transcription of the ethA gene, which encodes a monooxygenase enzyme required to activate the prodrug ethionamide into its bactericidal form (PubMed: 10613924). By binding to the operator region of the ethA promoter, EthR limits the intracellular concentration of EthA, thereby restricting the activation of ethionamide and contributing to the bacterium's innate resistance (PubMed: 19164740). EthR has emerged as a key therapeutic target for "booster" drugs, such as the BDM series of compounds and SMARt-420, designed to inhibit its repressor activity (PubMed: 27001551). This inhibition leads to the over-expression of EthA and a significant increase in ethionamide potency, potentially allowing for lower clinical doses and reduced toxicity in the treatment of multi-drug resistant tuberculosis. Related regulators in the TetR family also control various metabolic and efflux processes in mycobacteria, making this class of proteins a focal point for overcoming antibiotic resistance.

Other names

EthRRv3855H37Rv_3855TetR-family transcriptional repressor EthR

Inhibition of the EthR repressor protein leads to the de-repression of the ethA gene, resulting in increased levels of the EthA enzyme which activates the prodrug ethionamide.