DosR-DosS-DosT two-component regulatory system (DosRST)

The DosRST system is a critical two-component regulatory pathway in Mycobacterium tuberculosis (Mtb) that enables the bacterium to sense and adapt to host-induced environmental stresses such as hypoxia, nitric oxide (NO), and carbon monoxide (CO). It consists of two sensor histidine kinases, DosS and DosT, which detect these signals and a cognate response regulator, DosR, which orchestrates the expression of approximately 50 genes known as the dormancy regulon. This system is essential for Mtb to enter a state of non-replicating persistence (NRP), allowing it to survive for long periods within the host granuloma and develop high tolerance to standard antibiotics like isoniazid. Because NRP bacteria are a primary driver of the lengthy six-month tuberculosis treatment course, DosRST is a promising therapeutic target for adjunct therapies aimed at shortening treatment by eliminating the persistent bacterial reservoir. Experimental inhibitors have been identified that disrupt the pathway through various mechanisms, including targeting the sensor heme groups, inhibiting kinase autophosphorylation, or preventing DosR from binding to DNA.

Other names

DevR-DevS-DosT systemDosRS systemDormancy survival regulon systemDosR regulonTwo-component system DosRST

Inhibition of sensor kinase (DosS/DosT) autophosphorylation, oxidation or alkylation of the sensor kinase heme group, inhibition of phosphotransfer to DosR, and inhibition of DosR DNA binding.