Repurposing Hsp90 inhibitors as antibiotics targeting histidine kinases
| Autor: | Lindsey J. Moran, Jimmy A. Blair, Garrick H. Gu, Thomas E. Frederick, Bryn Falahee, Rebecca A. Dryer, Tony P. Huang, Hanna L. Shebert, Chau D. Vo, James F. Heinl, John W. Hammond, Shannon Zikovich, Peter D. Young, Taylor N. Jackvony, Douglas R. Wassarman, Juno Cho |
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| Rok vydání: | 2017 |
| Předmět: |
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Molecular 0301 basic medicine Histidine Kinase ATPase 030106 microbiology Clinical Biochemistry Pharmaceutical Science Microbial Sensitivity Tests Gram-Positive Bacteria Biochemistry Structure-Activity Relationship 03 medical and health sciences Gram-Negative Bacteria Drug Discovery Humans HSP90 Heat-Shock Proteins Protein Kinase Inhibitors Molecular Biology Histidine Dose-Response Relationship Drug Molecular Structure biology Chemistry Caulobacter crescentus Kinase Organic Chemistry Histidine kinase biology.organism_classification Hsp90 Two-component regulatory system Anti-Bacterial Agents 030104 developmental biology biology.protein Molecular Medicine Binding domain |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 27:5235-5244 |
| ISSN: | 0960-894X |
| Popis: | To address the growing need for new antimicrobial agents, we explored whether inhibition of bacterial signaling machinery could inhibit bacterial growth. Because bacteria rely on two-component signaling systems to respond to environmental changes, and because these systems are both highly conserved and mediated by histidine kinases, inhibiting histidine kinases may provide broad spectrum antimicrobial activity. The histidine kinase ATP binding domain is conserved with the ATPase domain of eukaryotic Hsp90 molecular chaperones. To find a chemical scaffold for compounds that target histidine kinases, we leveraged this conservation. We screened ATP competitive Hsp90 inhibitors against CckA, an essential histidine kinase in Caulobacter crescentus that controls cell growth, and showed that the diaryl pyrazole is a promising scaffold for histidine kinase inhibition. We synthesized a panel of derivatives and found that they inhibit the histidine kinases C. crescentus CckA and Salmonella PhoQ but not C. crescentus DivJ; and they inhibit bacterial growth in both Gram-negative and Gram-positive bacterial strains. |
| Databáze: | OpenAIRE |
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