Journal
NATURE CHEMICAL BIOLOGY
Volume 13, Issue 2, Pages 218-225Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2259
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Funding
- New England Regional Center of Excellence [U54 AI057159]
- Institute of Chemistry and Cell Biology (ICCB) at Harvard Medical School
- Ella and Hans Vahlteich Fund
- Beverly Vahlteich Delaney
- Michigan State University and AgBioResearch
- NIH-NIAID [R21A1105867]
- Grand Challenges Explorations awards from the Bill & Melinda Gates Foundation [OPP1059227, OPP1119065]
- Bill and Melinda Gates Foundation [OPP1059227, OPP1119065] Funding Source: Bill and Melinda Gates Foundation
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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.
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