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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Korbee CJ,Heemskerk MT,Kocev D,van Strijen E,Rabiee O,Franken KLMC,Wilson L,Savage NDL,Džeroski S,Haks MC,Ottenhoff THM

doi

10.1038/s41467-017-02777-6

subject

Has Abstract

pub_date

2018-01-24 00:00:00

pages

358

issue

1

issn

2041-1723

pii

10.1038/s41467-017-02777-6

journal_volume

9

pub_type

杂志文章

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