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Review
. 2020 Mar;12(5):457-467.
doi: 10.4155/fmc-2019-0263. Epub 2020 Feb 13.

Inhibiting DosRST as a new approach to tuberculosis therapy

Huiqing Zheng  1 , Robert B Abramovitch  1
Affiliations
Review

Inhibiting DosRST as a new approach to tuberculosis therapy

Huiqing Zheng et al. Future Med Chem. 2020 Mar.

Abstract

Progress against tuberculosis (TB) requires faster-acting drugs. Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious disease and its treatment is challenging and lengthy. Mtb is remarkably successful, in part, due to its ability to become dormant in response to host immune pressures. The DosRST two-component regulatory system is induced by hypoxia, nitric oxide and carbon monoxide and remodels Mtb physiology to promote nonreplicating persistence (NRP). NRP bacteria are thought to play a role in the long course of TB treatment. Therefore, inhibitors of DosRST-dependent adaptation may function to kill this reservoir of persisters and potentially shorten therapy. This review examines the function of DosRST, newly discovered compounds that inhibit DosRST signaling and considers future development of DosRST inhibitors as adjunct therapies.

Keywords: antivirulence therapies; drug discovery and development; drug tolerance; tuberculosis; two-component regulatory systems.

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Conflict of interest statement

Financial & competing interests disclosure

This project was supported by the Bill and Melinda Gates Foundation (grant no. OPP1059227 and OPP1119065) and the National Institute of Allergy and Infectious Diseases (grant no. R01AI116605 and R21AI105867). RB Abramovitch is the founder of Tarn Biosciences, a company developing new TB drugs. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
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 DevRN 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.
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.
See this image and copyright information in PMC

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