Inhibiting DosRST As a New Approach to Tuberculosis Therapy

Figures & data

Figure 1. Schematic for the DosRST signaling pathway, with examples of where small molecules and peptides interfere with DosRST signaling.

Artemisinin and HC106A target DosST heme to inhibit the sensing domain. Peptides A-ext and D, and small molecules HC102A and HC103A inhibit histidine kinase autophosphorylation. Peptide DevR_N inhibits phosphotransfer from DosS to DosR. Phenylcoumarin compound 10 and HC104A inhibit DosR DNA-binding. These compounds inhibit expression of DosR-regulated genes and inhibit survival during hypoxia, with the exception of HC104A. Compounds HC101A–HC106 were identified using a reporter strain where the DosR-regulated promoter, hspX, was cloned upstream of green fluorescent protein (GFP). Whole cell screening of a library of >540,000 compounds for inhibitors of hypoxia-inducible GFP fluorescence was conducted to discover DosRST inhibitors.

CO: Carbon monoxide; GFP: Green fluorescent protein; NO: Nitric oxide; TAG: Triacylglycerol.

Figure 2. Selected chemical structures of small molecules that inhibit DosRST signaling.

(A) Inhibitors of DosR. Compound 10 and HC104A inhibit DosR binding of promoter DNA. (B) Inhibitors of DosS and DosT. Artemisinin and HC106A inhibit DosS and DosT by interacting with the embedded heme sensor. HC102A and HC103A do not inhibit heme redox, but instead inhibit sensor kinase autophosphorylation.