Ethionamide resistance repressor (EthR) (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 (EthA). Because EthA is the enzyme responsible for activating the pro-drug ethionamide into its antimicrobial form, EthR effectively limits the efficacy of this second-line tuberculosis treatment. High levels of EthR activity contribute to the inherent and acquired resistance of M. tuberculosis to thioamides (UniProt P9WMC1; PMID: 12563273). In drug development, EthR is utilized as a target for "boosters"—small molecules that inhibit its DNA-binding capability. By preventing EthR from repressing the ethA promoter, these inhibitors increase the production of EthA, thereby enhancing the intracellular activation of ethionamide. This strategy, often referred to as "Small Molecule Aborting Resistance" (SMARt), aims to lower the effective dose of ethionamide required for treatment, potentially reducing the severe side effects associated with high-dose thioamide therapy and overcoming drug resistance in multi-drug resistant strains (PMID: 28212173; PMID: 30129881).

Other names

Transcriptional repressor EthRTetR-family transcriptional regulator EthRETH_REPR

Drugs targeting EthR act as small-molecule inhibitors that bind to its hydrophobic pocket, inducing a conformational change that prevents EthR from binding to the operator region of the ethA gene. This leads to the derepression and subsequent overexpression of the monooxygenase EthA, which bioactivates the pro-drug ethionamide into its toxic form (ethionamide-NAD adduct), thereby sensitizing the bacteria to the antibiotic.