The DOI matches its Crossref record; 55 of the 56 references it cites were found in a registry or an index.
Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence
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.
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Metadata
- Authors
- Zheng, H., Colvin, C. J., Johnson, B. K., Kirchhoff, P. D., Wilson, M., Jorgensen-Muga, K., Larsen, S. D., & Abramovitch, R. B.
- Affiliations
- Michigan State University (US)
- University of Michigan (US)
- Sweet Briar College (US)
- Corresponding author
- Abramovitch, Robert B
- Venue
- Nature Chemical Biology
- Published
- 2016-12-19
- Volume
- 13
- Issue
- 2
- Pages
- 218-225
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2563595958
- Cited by
- 169
- References
- 56
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 20 · 2023: 19 · 2022: 27 · 2021: 17 · 2020: 15 · 2019: 24 · 2018: 15 · 2017: 9
- FWCI
- 14.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (U54AI057159, R21AI105867)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
- Keywords
- Mycobacterium tuberculosis, non-replicating persistence, dormancy regulation, artemisinin, triglyceride synthesis, antibiotic tolerance, hypoxia, tuberculosis drug discovery, small molecule inhibitors
- MeSH terms
- Histidine Kinase, Dose-Response Relationship, Drug, Mycobacterium tuberculosis, Structure-Activity Relationship, Molecular Structure, Signal Transduction, Artemisinins, Protein Kinase Inhibitors, Drug Discovery
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