Histidine kinases of bacterial two-component systems are promising antibacterial targets. Despite their varied, numerous roles, enzymes in the histidine kinase superfamily share a catalytic core that may be exploited to inhibit multiple histidine kinases simultaneously. Characterized by the Bergerat fold, the features of the histidine kinase ATP-binding domain are not found in serine/threonine and tyrosine kinases. However, because each kinase family binds the same ATP substrate, we sought to determine if published serine/threonine and tyrosine kinase inhibitors contained scaffolds that would also inhibit histidine kinases. Using select assays, 222 inhibitors from the Roche Published Kinase Set were screened for binding, deactivation, and aggregation of histidine kinases. Not only do the results of our screen support the distinctions between ATP-binding domains of different kinase families, but the lead molecule identified also presents inspiration for further histidine kinase inhibitor development.
Bibliographical noteFunding Information:
We are grateful to Hoffmann-La Roche Inc. for providing the kinase inhibitor library. We thank S. Francis for synthesis of ADP-BODIPY. We thank M. Goswami for helpful discussions. We thank A. Zlotnick and L. Li for use and help with a microplate reader for assay development. Indiana University’s Physical Biochemistry Instrumentation Facility and the Indiana Molecular Biology Institute provided essential instrumentation. We thank M. Winkler for an overexpression strain for the VicK construct. This work was supported by the National Institutes of Health (NIH) DP2OD008592 , a Pew Biomedical Scholar Award (E.E.C.), an Indiana University Dean’s Fellowship (E.E.C.), and an Indiana University Quantitative and Chemical Biology training fellowship (K.E.W.) and the University of Minnesota . A
© 2018 Elsevier Ltd
- Antibacterial targets
- Histidine kinases
- Roche Published Kinase Set
- Two-component systems