Mycobacterium tuberculosis EthR2 transcriptional repressor (EthR2)

The Mycobacterium tuberculosis EthR2 transcriptional repressor (Rv3167c) is a member of the TetR family of regulators that plays a critical role in the metabolic activation of the second-line antitubercular prodrug ethionamide [UniProt, P9WIA1]. EthR2 specifically represses the expression of the ethA2 gene (Rv3169), which encodes a Baeyer-Villiger monooxygenase capable of converting ethionamide into its active, mycobactericidal form [PubMed, 22343615]. By inhibiting EthR2, the expression of ethA2 is induced, thereby enhancing the activation of ethionamide and potentially overcoming resistance mechanisms associated with the primary activator, EthA [PubMed, 35104045]. This makes EthR2 an attractive target for booster compounds designed to increase the efficacy and lower the required dose of ethionamide, which is often limited by dose-dependent toxicity in patients [Nature Communications, 2022]. Research into EthR2 inhibitors, such as BDM41906, aims to provide a synergistic approach to treating multidrug-resistant tuberculosis (MDR-TB) [Journal of Medicinal Chemistry, 2020].

Other names

Rv3167cTetR-family transcriptional repressor Rv3167cEthR2 repressor

Small molecule inhibitors bind to the EthR2 repressor, preventing it from binding to the operator region of the ethA2 gene, which results in increased expression of the EthA2 monooxygenase and subsequent activation of the prodrug ethionamide.