Mycobacterium tuberculosis MarR family transcription factor Rv0737 regulates bacterial growth and lipid synthesis by targeting the sigL-rslA operon.

The MarR family of transcription factors in Mycobacterium tuberculosis plays a critical role in bacterial adaptation to host stresses, yet the function of many members remains unknown. Here, we characterize the novel MarR regulator Rv0737 and its homolog Ms_1492 in M. smegmatis. Overexpression of Rv0737 severely impaired bacterial growth, cell division, and biofilm formation, while increasing susceptibility to oxidative stress and the cell wall-targeting drug isoniazid. Conversely, deletion of ms_1492 altered cell envelope permeability and lipid composition, enhanced ATP synthesis, and conferred mild tolerance to H2O2 and isoniazid. Lipid profiling and transcriptomic analysis revealed significant dysregulation of lipid metabolism genes. Crucially, electrophoretic mobility shift assays demonstrated that both Rv0737 and Ms_1492 directly bind to the promoter region of the sigL-rslA operon, which encodes an alternative sigma factor and its anti-sigma factor. Our findings establish a direct regulatory pathway wherein Rv0737/Ms_1492 modulates bacterial growth, cell envelope integrity, and stress response by targeting the sigL-rslA operon, identifying this system as a potential therapeutic target for combating drug-resistant tuberculosis.