Ethambutol-regulated repressor (EtbR)

EtbR, encoded by the gene Rv0273c, is a TetR-family transcriptional repressor in Mycobacterium tuberculosis that plays a pivotal role in regulating the expression of the inhA gene. The inhA gene encodes enoyl-acyl carrier protein reductase, an essential enzyme in the fatty acid synthase II (FAS-II) system required for the synthesis of mycolic acids, which are critical components of the mycobacterial cell wall. InhA is the primary molecular target for the first-line anti-tuberculosis drug isoniazid. EtbR has been identified as a novel ethambutol-binding protein; when ethambutol binds to EtbR, it enhances the repressor's affinity for the inhA promoter, leading to decreased production of the InhA enzyme. This molecular mechanism explains the synergistic effect observed between ethambutol and isoniazid, as the reduction in InhA levels makes the pathogen significantly more susceptible to isoniazid-mediated inhibition. Understanding EtbR is essential for characterizing drug resistance, as mutations in this regulator can lead to InhA overexpression and reduced drug efficacy. As a bacterial-specific transcription factor, EtbR represents a potential target for adjuvant therapies designed to potentiate existing anti-tuberculosis regimens.

Other names

Rv0273cTetR family transcriptional regulator Rv0273cInhA transcriptional repressor

Ethambutol acts as a ligand that binds to the EtbR repressor, stimulating its DNA-binding activity to the inhA promoter region, which leads to the transcriptional repression of the inhA gene and a subsequent increase in bacterial sensitivity to isoniazid.