OxiR specifically responds to isoniazid and regulates isoniazid susceptibility in mycobacteria

The bacteria drug resistance is not only associated with the gain of drug resistance gene but also relied on the adaptation of bacterial cells to antibiotics by transcriptional regulation. However, only a few transcription factors that regulate drug resistance have been characterized in mycobacteria. In this study, a TetR family transcriptional factor (OxiR), encoded by Rv0067c in Mycobacterium tuberculosis, was found to be an isoniazid (INH) resistance regulator. Comparing with the wild-type strain, the oxiR overexpressing strain is four times resistant to INH, whereas the oxiR knockout strain is eight times sensitive to INH. However, the rifamycin and ethambutol resistance were not influenced by oxiR. OxiR can bind to self-promoter at a 66 bp imperfect palindromic motifs. Interestingly, OxiR directly binds to INH, and thereby alleviate the self-repression. Furthermore, OxiR negatively regulated an oxidoreductase encoded by Rv0068. And the susceptibility of the Rv0068-overexpressing and oxiR knockout strains to all the three above-mentioned anti-tuberculosis drugs was equivalent, suggesting that the effect of oxiR to INH susceptibility is attributed to the derepression of Rv0068. In conclusion, we showed that OxiR can specifically modulate INH susceptibility by regulating an oxidoreductase encoding gene, both of which have not been associated with drug-resistance previously.