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
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DOI：
10.1038/s41467-017-02777-6
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发表时间：
2018-01-24
影响因子：
16.6
通讯作者：
Ottenhoff, Tom H. M.
中科院分区：
文献类型：
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作者：
Korbee, Cornelis J.;Heemskerk, Matthias T.;Ottenhoff, Tom H. M.
抗生素耐药性在对抗多药耐药（MDR）感染性疾病（如MDR结核病）方面造成了迅速增加的全球问题，促使包括宿主导向疗法（HDT）在内的新方法。细胞内病原体如沙门氏菌和结核分枝杆菌（Mtb）利用宿主途径生存。目前已知的靶向宿主途径的HDT化合物非常少。在基于药物再利用筛选的药物活性化合物库（LOPAC）中，我们鉴定了多种化合物，其靶向受体酪氨酸激酶（RTK）并且比目前已知的HDT化合物更有效地抑制细胞内Mtb和沙门氏菌。通过基于来自公共数据库的确认的靶标开发数据驱动的计算机模型，我们成功地预测了其他有效的HDT化合物。这些化合物靶向宿主RTK信号传导并抑制细胞内（MDR）Mtb。互补的人激酶组siRNA筛选独立地证实了RTK信号传导和激酶（BLK、ABL1和NTRK1）在Mtb的宿主控制中的作用。这些方法验证了RTK信号传导作为针对细胞内细菌的HDT的可药用宿主途径。
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.