Combined chemical genetics and data-driven bioinformatics approach identifies receptor tyrosine kinase inhibitors as host-directed antimicrobials
| Autor: | Omid Rabiee, Mariëlle C. Haks, Cornelis J. Korbee, Dragi Kocev, Matthias T. Heemskerk, Louis Wilson, Tom H. M. Ottenhoff, Elisabeth van Strijen, Nigel D. L. Savage, Kees L. M. C. Franken, Sašo Džeroski |
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| Rok vydání: | 2018 |
| Předmět: |
Salmonella typhimurium
0301 basic medicine Science In silico Receptor Protein-Tyrosine Kinases General Physics and Astronomy Computational biology Article General Biochemistry Genetics and Molecular Biology Receptor tyrosine kinase Cell Line 03 medical and health sciences 0302 clinical medicine Drug Resistance Bacterial Humans Tuberculosis Kinome Enzyme Inhibitors lcsh:Science Multidisciplinary ABL biology Intracellular parasite Computational Biology Mycobacterium tuberculosis General Chemistry Anti-Bacterial Agents 3. Good health 030104 developmental biology 030220 oncology & carcinogenesis Host-Pathogen Interactions Salmonella Infections biology.protein lcsh:Q Signal transduction Chemical genetics Signal Transduction |
| Zdroj: | Nature Communications Nature Communications, 9 Nature Communications, Vol 9, Iss 1, Pp 1-14 (2018) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-017-02777-6 |
| Popis: | Antibiotic resistance poses rapidly increasing global problems in combatting multidrug-resistant (MDR) infectious diseases like MDR tuberculosis, prompting for novel approaches including host-directed therapies (HDT). Intracellular pathogens like Salmonellae and Mycobacterium tuberculosis (Mtb) exploit host pathways to survive. Only very few HDT compounds targeting host pathways are currently known. In a library of pharmacologically active compounds (LOPAC)-based drug-repurposing screen, we identify multiple compounds, which target receptor tyrosine kinases (RTKs) and inhibit intracellular Mtb and Salmonellae more potently than currently known HDT compounds. By developing a data-driven in silico model based on confirmed targets from public databases, we successfully predict additional efficacious HDT compounds. These compounds target host RTK signaling and inhibit intracellular (MDR) Mtb. A complementary human kinome siRNA screen independently confirms the role of RTK signaling and kinases (BLK, ABL1, and NTRK1) in host control of Mtb. These approaches validate RTK signaling as a drugable host pathway for HDT against intracellular bacteria. Multidrug resistance necessitates novel approaches to treating bacterial infections. Here, the authors apply their high-throughput screening and in silico prediction approaches to show that host receptor tyrosine kinases are good targets for host-directed therapies against intracellular bacteria. |
| Databáze: | OpenAIRE |
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