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

Cornelis J. Korbee, Matthias T. Heemskerk, Dragi Kocev, Elisabeth Strijen, Omid Rabiee, Kees L. M. C. Franken, Louis Wilson, Nigel D. L. Savage, Sašo Džeroski, Mariëlle C. Haks () and Tom H. M. Ottenhoff ()
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Cornelis J. Korbee: Leiden University Medical Center
Matthias T. Heemskerk: Leiden University Medical Center
Dragi Kocev: Jožef Stefan Institute
Elisabeth Strijen: Leiden University Medical Center
Omid Rabiee: Leiden University Medical Center
Kees L. M. C. Franken: Leiden University Medical Center
Louis Wilson: Leiden University Medical Center
Nigel D. L. Savage: Leiden University Medical Center
Sašo Džeroski: Jožef Stefan Institute
Mariëlle C. Haks: Leiden University Medical Center
Tom H. M. Ottenhoff: Leiden University Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02777-6

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