HTH-type transcriptional regulator EthR2 (Rv0078) (EthR2)

EthR2 (Rv0078) is an HTH-type transcriptional regulator in Mycobacterium tuberculosis that serves as a key control point for ethionamide bioactivation. This transcriptional repressor negatively regulates genes involved in the metabolism and activation of ethionamide, a second-line antitubercular drug used to treat multidrug-resistant tuberculosis. Unlike the primary EthR regulator, EthR2 represents an alternative regulatory pathway that controls ethionamide activation. Small-molecule inhibitors of EthR2 function as ethionamide boosters by preventing the repressor from binding to DNA, thereby derepressing the bioactivation pathway and enhancing the drug's antimycobacterial activity. This mechanism allows for reduced ethionamide doses while maintaining efficacy, potentially decreasing the gastrointestinal toxicity and tolerability issues associated with higher therapeutic doses. EthR2 inhibitors such as BDM76060 and BDM76150 have demonstrated enhanced binding affinity and superior boosting capacity in preclinical studies, positioning EthR2 as an attractive therapeutic target for improving multidrug-resistant tuberculosis treatment outcomes.

Other names

EthR2 (Rv0078)Transcriptional repressor EthR2Second ethionamide transcriptional repressor

Small-molecule inhibitors of EthR2 bind to the protein and abolish its DNA-binding ability, preventing it from repressing genes involved in ethionamide bioactivation. This derepresses an alternative ethionamide bioactivation pathway, allowing increased activation of the pro-drug. EthR2 inhibitors act as boosters that increase the bioactivation and antimycobacterial activity of ethionamide.