HTH-type transcriptional regulator EthR (and EthR2 for the paralog) (EthR; EthR2)

HTH-type transcriptional regulator EthR is a Mycobacterium tuberculosis (M. tuberculosis) protein belonging to the TetR family of repressors, characterized by a helix-turn-helix (HTH) DNA-binding motif. EthR represses the expression of EthA, a monooxygenase required for activation of ethionamide, a prodrug used to treat multidrug-resistant tuberculosis. By inhibiting EthR (or the related EthR2 paralog), the expression of EthA (or analogous enzymes) is increased, resulting in enhanced activation and efficacy of ethionamide and related prodrugs. EthR is targeted by several experimental ligands, which bind and induce conformational changes that prevent DNA binding, thereby derepressing gene expression. EthR2, a paralog, regulates a distinct but related bioactivation pathway, and can be targeted by small molecules such as SMARt-420. These regulators are considered promising targets for adjunctive therapies to overcome drug resistance in tuberculosis by boosting the activation of existing prodrugs.

Other names

EthREthR2Transcriptional repressor EthRTetR family transcriptional repressor EthR

Inhibition of EthR/EthR2 leads to derepression of EthA or related monooxygenases, enabling/enhancing prodrug (ethionamide) activation. Direct binding of small molecules to EthR/EthR2 alters their conformation, preventing DNA binding and thus derepressing target gene expression.