Figure 3
From: Identification of kinase inhibitors as potential host-directed therapies for intracellular bacteria
Identification of HDT targets against intracellular Mtb through combined chemical and genetic inhibition of host kinases. (a) Each circle in the phylogenetic tree depicts host kinases that are relevant for HDT against intracellular Mtb by combining data from chemical19,20 and genetic6 kinase inhibition screens. The effect of chemical inhibition of kinase targets is represented by circle size, which corresponds to the number of Mtb hit compounds that inhibit a kinase by > 50%51. The effect of genetic inhibition of kinase targets, using a siRNA knockdown screen of host kinases in Mtb-infected MelJuSo cells, is shown by color with the most relevant targets in Mtb survival shown in green in green for relevant targets involved in Mtb survival, while likely off-targets are shown in black. White circles represent targets for which genetic inhibition was not available. (b) All 17 Mtb hit compounds were clustered according to chemotype and chemical similarity, using the Tanimoto coefficient as a similarity measure with cut-off value of 0.551. (c) Chemical structures of Mtb hit compounds belonging to the chemotype of morpholino-imidazo/triazolo-pyrimidinones. (d) Inhibition of phosphatidyl inositol 3-kinases by morpholino-imidazo/triazolo-pyrimidinone hit compounds. (e) Effect of genetic inhibition of phosphatidyl inositol 3-kinases on the bacterial burden of Mtb-infected MelJuSo cells. (f) Chemical structures of Mtb hit compounds belonging to the chemotype of 2-aminobenzimidazoles. (g) Inhibition of selected kinases by 2-aminobenzimidazole Mtb hit compounds. Only the five shared kinases that gave the strongest effect on intracellular Mtb upon knockdown are shown (see Supplementary Figure 4 for the whole list of 51 shared targets). (h) Effect of knockdown of the same kinase targets on the bacterial burden of Mtb-infected MelJuSo cells.
