Redox homeostasis in Mycobacterium tuberculosis is modulated by a novel actinomycete‐specific transcription factor

Mycobacterium tuberculosis (Mtb) has evolved diverse cellular processes in response to the multiple stresses it encounters within the infected host. We explored available TnSeq datasets to identify transcription factors (TFs) that are essential for Mtb survival inside the host. The analysis identified a single TF, Rv1332 (AosR), conserved across actinomycetes with a so‐far uncharacterized function. AosR mitigates phagocyte‐derived oxidative and nitrosative stress, thus promoting mycobacterial growth in the murine lungs and spleen. Oxidative stress induces formation of a single intrasubunit disulphide bond in AosR, which in turn facilitates AosR interaction with an extracytoplasmic‐function sigma factor, SigH. This leads to the specific upregulation of the CysM‐dependent non‐canonical cysteine biosynthesis pathway through an auxiliary intragenic stress‐responsive promoter, an axis critical in detoxifying host‐derived oxidative and nitrosative radicals. Failure to upregulate AosR‐dependent cysteine biosynthesis during the redox stress causes differential expression of 6% of Mtb genes. Our study shows that the AosR‐SigH pathway is critical for detoxifying host‐derived oxidative and nitrosative radicals to enhance Mtb survival in the hostile intracellular environment.