Fig. 6 | Nature Communications

Fig. 6

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

Fig. 6

Identification of host kinases controlling intracellular Mtb survival. a STRING network of confirmed targets of dovitinib retrieved from the ChEMBL repository Compound Bioactivity section (left panel). Individual proteins are displayed as nodes. Lines represent protein–protein interactions and the thickness of the lines indicates confidence. Proteins participating in the “transmembrane receptor tyrosine kinase signaling pathway” are displayed in red. The top 10 enriched GO terms in the “Biological Function” category are displayed along with the number of genes/proteins annotated with the indicated GO terms and the false-discovery rate (FDR) of the enrichment (right panel). b Results of a siRNA screen of the human kinome in the MelJuSo-Mtb infection model using Mtb constitutively expressing destabilized DsRed, expressed as z-scores. The average z-score ± standard deviation for each siRNA pool is displayed. A hit cutoff at z = 2 or z = –2 is displayed as a dashed line. The average z-score and standard deviation of the controls (siCTRL and siAKT) are displayed separately. SiCTRL: nontargeting siRNA pool. c STRING network of the siRNA screen hits (left panel) is displayed along the top 10 enriched GO terms in the “Biological Function” category (right panel), as in a. d Participation of individual targets of dovitinib (top row) or hits from the siRNA screen (bottom row) in the “transmembrane receptor tyrosine kinase signaling pathway” are indicated by filled squares. Proteins that are both targeted by dovitinib and were a hit in the siRNA screen are shown in magenta. Dissociation constants (K i ) retrieved from ChEMBL are shown below for the interaction between dovitinib and ABL1, BLK, and NTRK1. e STRING analysis to identify enriched KEGG pathways using the kinases from d. The top 10 enriched KEGG pathways along with the number of genes/proteins annotated with the indicated GO terms and the FDR of the enrichment are displayed (left panel). Involvement of individual proteins is overlaid on the “neurotrophin signaling pathway” KEGG pathway retrieved from the Kyoto Encyclopedia of Genes and Genomes (http://www.genome.jp/kegg/). Proteins in gray are targeted by dovitinib only, blue proteins were siRNA screening hits, and proteins in red are both targeted by dovitinib and silencing of these genes affected the Mtb bacterial load

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