The ability of Mycobacterium tuberculosis (Mtb) to persist in the host complicates and prolongs tuberculosis (TB) treatment. Our recent work on host-pathogen communication revealed the critical reliance on quality assimilation of situational “data” for intracellular pathogens such as Mtb. TcrXY, is an autoregulated acid-sensing two-component system (TCS) of Mtb, identified as controlling a functionally diverse regulon required for persistence. Two representatives of this regulon, Rv3706c and Rv3705A, are implicated as key determinants for the survival of Mtb within macrophages by serving as important effectors to mitigate redox stress at acidic pH. CRISPRi genetic silencing of the response regulator tcrX, attenuates the persistence of Mtb during chronic mouse infection and improves treatment with the two front-line anti-TB drugs, rifampicin and isoniazid. Finally, the utility of CRISPRi as highly efficient and effective tool for bacterial gene silencing during mouse infection will be discussed, including a powerful approach to demonstrate draggability of a target, without the need for an specific small molecule inhibitor being first developed.