Background: The Dormancy survival regulator (DosR), Rv3133c, is one of the key transcriptional proteins that regulate the dormancy of Mycobacterium tuberculosis (MTB), participates in various metabolic processes, and is essential for the survival of MTB in the host. MRA₀776 (homologous with Rv0767c and MSMEG₅860) belongs to the TetR family of regulators; we previously found that MRA₀776 can directly regulate the expression of dosR, although the mechanism by which MRA₀776 acts directly on dosR and other small molecules affecting the interaction of MRA₀776 with dosR has not been elucidated. Results: In the present study, primary transcriptomic analysis of a MRA₀776 overexpression strain revealed that MRA₀776 is a broad-spectrum regulatory protein and that MRA₀776 specifically binds to the dosR promoter both in vitro and in vivo. In addition, we found that a range of ligands, including lysine, arginine, tyrosine, Cu2+, Fe3+ and Pb2+, inhibited the interaction of MRA₀776 with the dosR promoter. Furthermore, molecular docking predicted that 125-Thr is likely to be a key amino acid site for the interaction of MRA₀776 with ligands. Finally, MRA₀776 promoted bacteria colonization and induced pathological damage in livers, spleens, lungs, and kidneys in mice. Conclusions: In conclusion, our analyses suggested that MRA₀776 is a pleiotropic regulator, and its overexpression can promote colonization and pathogenicity of MTB.
Wang et al. (Fri,) studied this question.