title: 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.
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Colvin
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Johnson
authors.affiliation: Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kirchhoff
authors.affiliation: Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Sweet Briar College, Sweet Briar, Virginia, USA.
authors.forename: Katriana
authors.initials: K
authors.lastname: Jorgensen-Muga
authors.affiliation: Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Abramovitch
mesh_terms: D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D000071677:Histidine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D037621:Artemisinins; D047428:Protein Kinase Inhibitors; C031327:artemisinin; D000071677:Histidine Kinase