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Tuberculosis (TB) caused by  Mycobacterium tuberculosis  ( Mtb ) accounts for nearly 1.2 million deaths per annum worldwide. Due to the emergence of multidrug-resistant (MDR)  Mtb  strains, TB, a curable and avertable disease, remains one of the leading causes of morbidity and mortality. Isoniazid (INH) is a first-line anti-TB drug while ethionamide (ETH) is used as a second-line anti-TB drug. INH and ETH resistance develop through a network of genes involved in various biosynthetic pathways. In this study, we identified Rv0023, an  Mtb  protein belonging to the xenobiotic response element (XRE) family of transcription regulators, which has a role in generating higher tolerance toward INH and ETH in  Mycobacterium smegmatis  ( Msmeg ). Overexpression of Rv0023 in  Msmeg  leads to the development of INH- and ETH-tolerant strains. The strains expressing Rv0023 have a higher ratio of NADH/NAD + , and this physiological event is known to play a crucial role in the development of INH/ETH co-resistance in  Msmeg . Gene expression analysis of some target genes revealed reduction in the expression of the  ndh  gene, but no direct interaction was observed between Rv0023 and the  ndh  promoter region.  Rv0023  is divergently expressed to  Rv0022c  ( whiB5 ) and we observed a direct interaction between the recombinant Rv0023 protein with the upstream region of  Rv0022c , confirmed using reporter constructs of  Msmeg . However, we found no indication that this interaction might play a role in the development of INH/ETH drug tolerance.

Ectopic Expression of Rv0023 Mediates Isoniazid/Ethionamide Tolerance via Altering NADH/NAD+ Levels in Mycobacterium smegmatis