Repurposing Eukaryotic Kinase Inhibitors as Colistin Adjuvants in Gram-Negative Bacteria
| Autor: | Sara M Brackett, William T. Barker, Robert K. Ernst, Courtney E. Chandler, Ansley M Nemeth, Akash Basak, Beverly H. Koller, Christian Melander, Roberta J. Melander, William J. Zuercher, Leigh A. Jania |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Gram-negative bacteria medicine.drug_class Polymyxin 030106 microbiology Microbial Sensitivity Tests Gram-Positive Bacteria Article Cell Line Lipid A 03 medical and health sciences chemistry.chemical_compound Drug Resistance Multiple Bacterial Gram-Negative Bacteria medicine Protein Kinase Inhibitors Adjuvants Pharmaceutic Sulfonamides Natural product biology Kinase Chemistry Colistin Eukaryota Pyruvate Dehydrogenase Acetyl-Transferring Kinase Potentiator biology.organism_classification I-kappa B Kinase Drug Combinations 030104 developmental biology Infectious Diseases Biochemistry Benzamides Pyrazoles Bacteria medicine.drug |
| Zdroj: | ACS Infect Dis |
| ISSN: | 2373-8227 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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