1. Academic Validation
  2. Combined chemical genetics and data-driven bioinformatics approach identifies receptor tyrosine kinase inhibitors as host-directed antimicrobials

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

  • Nat Commun. 2018 Jan 24;9(1):358. doi: 10.1038/s41467-017-02777-6.
Cornelis J Korbee 1 Matthias T Heemskerk 1 Dragi Kocev 2 Elisabeth van Strijen 1 Omid Rabiee 1 Kees L M C Franken 1 Louis Wilson 1 Nigel D L Savage 1 Sašo Džeroski 2 Mariëlle C Haks 3 Tom H M Ottenhoff 4
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands.
  • 2 Department of Knowledge Technologies, Jožef Stefan Institute, Jamova Cesta 39, Ljubljana, 1000, Slovenia.
  • 3 Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands. m.c.haks@lumc.nl.
  • 4 Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands. t.h.m.ottenhoff@lumc.nl.
Abstract

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.

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