Inactivation of multiple bacterial histidine kinases by targeting the ATP-binding domain

Kaelyn E. Wilke, Samson Francis, Erin E. Carlson

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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 ∼53000 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.

Original languageEnglish (US)
Pages (from-to)328-335
Number of pages8
JournalACS Chemical Biology
Volume10
Issue number1
DOIs
StatePublished - Jan 16 2015

Bibliographical note

Publisher Copyright:
© 2014 American Chemical Society.

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