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 H 2 O 2 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.