Figure 6. Increased 3′,5-cyclic adenosine monophosphate (cAMP) level and effective stress response versus decreased cAMP level and reduced stress tolerance of mycobacteria.

In this model, upon activation by an appropriate signal via the cognate sensor PhoR, P~PhoP binds to rv0805 regulatory region and functions as a specific repressor by preventing access for mycobacterial RNA polymerase (RNAP) to bind to the promoter and initiate transcription. In keeping with PhoP-dependent rv0805 repression, our results demonstrate a reproducibly lower level of cAMP in phoPR-KO relative to WT bacilli. Thus, phoPR-KO (or WT-Rv0805) remains ineffective to mount an appropriate stress response most likely due to its inability to coordinate regulated gene expression because of dysregulation of cAMP level, accounting for their reduced stress tolerance. Together, these molecular events suggest that failure to maintain cAMP level accounts for attenuated phenotype of the bacilli.