Combined chemical genetics and data-driven bioinformatics approach identifies receptor tyrosine kinase inhibitors as host-directed antimicrobials

• Published in: Nature communications 2018-01, Vol.9 (1), p.358-14, Article 358
• Main Authors: Korbee, Cornelis J., Heemskerk, Matthias T., Kocev, Dragi, van Strijen, Elisabeth, Rabiee, Omid, Franken, Kees L. M. C., Wilson, Louis, Savage, Nigel D. L., Džeroski, Sašo, Haks, Mariëlle C., Ottenhoff, Tom H. M.
• Format: Article
• Language: English
• Subjects: 13/106; 13/89; 13/95; 38/47; 49/31; 631/154/555; 631/250/255/1318; 631/250/255/1856; 631/92/360; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Antibiotics; Antimicrobial agents; Bacteria; Bioinformatics; Cell Line; Computational Biology; Cyclin-dependent kinases; Drug Resistance, Bacterial; Enzyme Inhibitors - pharmacology; Genetic screening; Genetics; Host-Pathogen Interactions - drug effects; Humanities and Social Sciences; Humans; Infectious diseases; Intracellular; Intracellular signalling; Kinases; multidisciplinary; Multidrug resistance; Multidrug resistant organisms; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - physiology; Pharmacology; Protein-tyrosine kinase receptors; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Salmonella Infections - enzymology; Salmonella Infections - genetics; Salmonella Infections - microbiology; Salmonella typhimurium - drug effects; Salmonella typhimurium - genetics; Salmonella typhimurium - physiology; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; siRNA; Target recognition; Tuberculosis; Tuberculosis - enzymology; Tuberculosis - genetics; Tuberculosis - microbiology; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02777-6

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.