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

Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence.

Author information

1
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.
2
Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
3
Sweet Briar College, Sweet Briar, Virginia, USA.

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.

PMID:
27992879
DOI:
10.1038/nchembio.2259
[Indexed for MEDLINE]

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