Ethambutol-responsive regulator (EtbR) (EtbR)

EtbR (Rv0273c) is a TetR-family transcriptional repressor in Mycobacterium tuberculosis that plays a critical role in regulating the expression of the inhA gene. The inhA gene encodes the enoyl-acyl carrier protein reductase, an essential enzyme in the fatty acid synthase type II (FAS-II) system required for the synthesis of mycolic acids, which are vital components of the mycobacterial cell wall. EtbR functions by binding to a specific motif in the upstream region of the inhA promoter, thereby inhibiting its transcription and controlling the levels of the InhA protein. Notably, EtbR has been identified as a target for the first-line anti-tuberculosis drug ethambutol, which acts as a ligand that enhances EtbR's DNA-binding affinity. This increased repression leads to reduced levels of the InhA protein, which is the primary target of another first-line drug, isoniazid. Consequently, the interaction between ethambutol and EtbR provides a molecular explanation for the synergistic bactericidal effect observed when ethambutol and isoniazid are used in combination therapy, as ethambutol-mediated repression of inhA increases the bacteria's sensitivity to isoniazid. EtbR also autoregulates its own expression and represents a significant point of intervention for optimizing combination therapies against tuberculosis.

Other names

Rv0273cTetR-family transcriptional regulator Rv0273cTranscriptional repressor of inhA

Ethambutol acts as a ligand that binds to the EtbR repressor, enhancing its DNA-binding activity and its ability to repress the transcription of the inhA gene. This reduction in InhA (enoyl-ACP reductase) protein levels increases the susceptibility of Mycobacterium tuberculosis to isoniazid, which also targets the InhA enzyme.