HTH-type transcriptional regulator EthR (EthR) (EthR)

EthR is a transcriptional repressor belonging to the TetR family, found in Mycobacterium tuberculosis (UniProt P9WMC1). It plays a critical role in regulating the sensitivity of the bacterium to the second-line antibiotic ethionamide by controlling the expression of the ethA gene (Baulard et al., 2000). EthA encodes a monooxygenase required to convert the prodrug ethionamide into its active form, which then inhibits the essential enoyl-ACP reductase InhA (Willand et al., 2009). By binding to the ethA operator, EthR limits the production of EthA, thereby contributing to innate and acquired resistance (Baulard et al., 2000). Small molecule inhibitors of EthR, often called "boosters," prevent EthR from binding to DNA, resulting in the overexpression of EthA and significantly enhancing the bactericidal activity of ethionamide (Willand et al., 2009; Flipo et al., 2012). This strategy aims to lower the effective dose of ethionamide required for treatment, potentially reducing the drug's side effects and overcoming resistance mechanisms (Flipo et al., 2012).

Other names

HTH-type transcriptional regulator EthREthR1Ethionamide resistance regulator

EthR inhibitors bind to the ligand-binding pocket of the EthR dimer, inducing a conformational change that prevents the protein from binding to the ethA promoter (Willand et al., 2009). This leads to the derepression of the ethA gene, increasing the production of the EthA monooxygenase, which activates the prodrug ethionamide (Flipo et al., 2012).