EthR

EthR is a transcriptional regulator in Mycobacterium tuberculosis. It is a member of the TetR family of repressors and acts as a cytosolic DNA-binding protein that controls the expression of ethA, a monooxygenase required to activate the antitubercular prodrug ethionamide.

Mechanism and regulation: EthR binds to the promoter region of ethA, repressing its transcription. Small-molecule ligands can bind to EthR and induce a conformational change that reduces its DNA-binding affinity, leading to derepression of ethA and higher levels of EthA enzyme. This regulatory axis links EthR activity to the activation of ethionamide.

Biological significance: By modulating EthA expression, EthR influences the efficacy of ethionamide, since EthA is needed to convert the prodrug into its active form. Variations in EthR activity can therefore affect the drug’s potency and therapeutic outcomes.

Therapeutic relevance: EthR inhibitors have been investigated as potential adjuvants to enhance ethionamide efficacy and address resistance in tuberculosis treatment. The strategy aims to increase EthA levels and drug activation, potentially improving outcomes in drug-susceptible and drug-resistant TB. Challenges include achieving specificity, avoiding off-target effects, and the potential emergence of new resistance mechanisms.

Structure and genetics: EthR is encoded in the M. tuberculosis genome and adopts a typical TetR-family fold, with an N-terminal helix-turn-helix DNA-binding domain and a C-terminal ligand-binding domain. Its ligand-binding pocket mediates the allosteric changes that govern DNA affinity and transcriptional control.