title: Inactivation of multiple bacterial histidine kinases by targeting the ATP-binding domain.
abstract: Antibacterial agents that exploit new targets will be required to combat the perpetual rise of bacterial resistance to current antibiotics. We are exploring the inhibition of histidine kinases, constituents of two-component systems. Two-component systems are the primary signaling pathways that bacteria utilize to respond to their environment. They are ubiquitous in bacteria and trigger various pathogenic mechanisms. To attenuate these signaling pathways, we sought to broadly target the histidine kinase family by focusing on their highly conserved ATP-binding domain. Development of a fluorescence polarization displacement assay facilitated high-throughput screening of ∼53 000 diverse small molecules for binding to the ATP-binding pocket. Of these compounds, nine inhibited the catalytic activity of two or more histidine kinases. These scaffolds could provide valuable starting points for the design of broadly effective HK inhibitors, global reduction of bacterial signaling, and ultimately, a class of antibiotics that function by a new mechanism of action.
authors.affiliation: Department of Chemistry, Indiana University , 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States.
authors.forename: Kaelyn E
authors.initials: KE
authors.lastname: Wilke
authors.forename: Samson
authors.initials: S
authors.lastname: Francis
authors.forename: Erin E
authors.initials: EE
authors.lastname: Carlson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects / Q000201:enzymology; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D005454:Fluorescence Polarization; D057166:High-Throughput Screening Assays; D000071677:Histidine Kinase; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D014709:Vero Cells
chemical_list: D000900:Anti-Bacterial Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D000071677:Histidine Kinase