Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence

• Published in: Nature chemical biology Vol. 13; no. 2; pp. 218 - 225
• Main Authors: Zheng, Huiqing, Colvin, Christopher J, Johnson, Benjamin K, Kirchhoff, Paul D, Wilson, Michael, Jorgensen-Muga, Katriana, Larsen, Scott D, Abramovitch, Robert B
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2017; Nature Publishing Group
• Subjects: 631/154/1435/2163; 631/154/1435/2417; 631/326/41; 631/92/609; Artemisinins - chemistry; Artemisinins - pharmacology; Bacteria; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cell Biology; Chemical compounds; Chemistry; Chemistry/Food Science; Dose-Response Relationship, Drug; Drug Discovery; Genotype & phenotype; Histidine Kinase - antagonists & inhibitors; Histidine Kinase - metabolism; Hypoxia; Inhibitors; Molecular Structure; Mycobacterium tuberculosis; Mycobacterium tuberculosis - enzymology; Physiology; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Signal transduction; Signal Transduction - drug effects; Structure-Activity Relationship; Survival; Tuberculosis
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/nchembio.2259

A high-throughput screen identifies inhibitors of the M. tuberculosis dormancy regulation system, DosRST, including compounds that inhibit autophosphorylation of the DosS and DosT sensor kinases and those that inhibit the catalytic heme of these kinases. 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.