Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence

Nat Chem Biol. 2017 Feb;13(2):218-225. doi: 10.1038/nchembio.2259. Epub 2016 Dec 19.

Abstract

The Mycobacterium tuberculosis (Mtb) DosRST two-component regulatory system promotes the survival of Mtb during non-replicating persistence (NRP). NRP bacteria help drive the long course of tuberculosis therapy; therefore, chemical inhibition of DosRST may inhibit the ability of Mtb to establish persistence and thus shorten treatment. Using a DosRST-dependent fluorescent Mtb reporter strain, a whole-cell phenotypic high-throughput screen of a ∼540,000 compound small-molecule library was conducted. The screen discovered novel inhibitors of the DosRST regulon, including three compounds that were subject to follow-up studies: artemisinin, HC102A and HC103A. Under hypoxia, all three compounds inhibit Mtb-persistence-associated physiological processes, including triacylglycerol synthesis, survival and antibiotic tolerance. Artemisinin functions by disabling the heme-based DosS and DosT sensor kinases by oxidizing ferrous heme and generating heme-artemisinin adducts. In contrast, HC103A inhibits DosS and DosT autophosphorylation activity without targeting the sensor kinase heme.

MeSH terms

  • Artemisinins / chemistry
  • Artemisinins / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Histidine Kinase / antagonists & inhibitors*
  • Histidine Kinase / metabolism
  • Molecular Structure
  • Mycobacterium tuberculosis / enzymology*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction / drug effects*
  • Structure-Activity Relationship

Substances

  • Artemisinins
  • Protein Kinase Inhibitors
  • artemisinin
  • Histidine Kinase

Associated data

  • PubChem-Substance/319551946
  • PubChem-Substance/319551947
  • PubChem-Substance/319551948
  • PubChem-Substance/319551949
  • PubChem-Substance/319551950