Autor: |
Rob Striker, John-Demian Sauer, Rebecca Procknow, B. Zuercher, David H. Drewry, Adam J. Schaenzer, Martin S. Pavelka, Nathan Wlodarchak, Kenneth A. Satyshur, Teachout N, Jeffrey Beczkiewicz |
Jazyk: |
angličtina |
Rok vydání: |
2017 |
Předmět: |
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DOI: |
10.1101/199422 |
Popis: |
Antibiotic resistant bacteria are an increasing global problem, and pathogenic actinomycetes and firmicutes are particularly challenging obstacles. These pathogens share several eukaryotic-like kinases that present antibiotic development opportunities. We used computational modelling to identify human kinase inhibitors that could be repurposed towards bacteria as part of a novel combination therapy. The computational model suggested a family of inhibitors, the imidazopyridine aminofurazans (IPAs), bind PknB with high affinity. We found that these inhibitors biochemically inhibit PknB, with potency roughly following the predicted models. A novel x-ray structure confirmed that the inhibitors bind as predicted and made favorable protein contacts with the target. These inhibitors also have antimicrobial activity towards Mycobacteria and Nocardia, and normally ineffective β-lactams can potentiate IPAs to more efficiently inhibit growth of these pathogens. Collectively, our data show thatin silicomodeling can be used as a tool to discover promising drug leads, and the inhibitors we discovered can synergize with clinically relevant antibiotics to restore their efficacy against bacteria with limited treatment options. |
Databáze: |
OpenAIRE |
Externí odkaz: |
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