Open AccessRepurposing Eukaryotic Kinase Inhibitors as Colistin Adjuvants in Gram-Negative Bacteria
Author(s) -
William T. Barker,
Ansley M Nemeth,
Sara M Brackett,
Abhishek Basak,
Courtney E. Chandler,
Leigh A. Jania,
William J. Zuercher,
Roberta J. Melander,
Beverly H. Koller,
Robert K. Ernst
Publication year - 2019
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.9b00212
Subject(s) - kinase , colistin , repurposing , polymyxin , bacteria , protein kinase a , pyruvate kinase , biology , gram negative bacteria , microbiology and biotechnology , biochemistry , chemistry , enzyme , antimicrobial , glycolysis , escherichia coli , antibiotics , ecology , genetics , gene
Kinase inhibitors comprise a diverse cohort of chemical scaffolds that are active in multiple biological systems. Currently, thousands of eukaryotic kinase inhibitors are commercially available, have well-characterized targets, and often carry pharmaceutically favorable toxicity profiles. Recently, our group disclosed that derivatives of the natural product meridianin D, a known inhibitor of eukaryotic kinases, modulated behaviors of both Gram-positive and Gram-negative bacteria. Herein, we expand our exploration of kinase inhibitors in Gram-negative bacilli utilizing three commercially available kinase inhibitor libraries and, ultimately, identify two chemical structures that potentiate colistin (polymyxin E) in multiple strains. We report IMD-0354, an inhibitor of IKK-β, as a markedly effective adjuvant in colistin-resistant bacteria and also describe AR-12 (OSU-03012), an inhibitor of pyruvate dehydrogenase kinase-1 (PDK-1), as a potentiator in colistin-sensitive strains. This report comprises the first description of the novel cross-reactivity of these molecules.