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Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1

机译:细胞内细菌的生长受PKB / AKT1周围的激酶网络控制

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With the emergence of multidrug resistant (MDR) bacteria, it is imperative to develop new intervention strategies. Current antibiotics typically target pathogen rather than host-specific biochemical pathways. Here we have developed kinase inhibitors that prevent intracellular growth of unrelated pathogens such as Salmonella typhimurium and Mycobacterium tuberculosis. An RNA interference screen of the human kinome using automated microscopy revealed several host kinases capable of inhibiting intracellular growth of S. typhimurium. The kinases identified clustered in one network around AKT1 (also known as PKB). Inhibitors of AKT1 prevent intracellular growth of various bacteria including MDR-M. tuberculosis. AKT1 is activated by the S. typhimurium effector SopB, which promotes intracellular survival by controlling actin dynamics through PAK4, and phagosome-lysosome fusion through the AS 160 (also known as TBC1D4)-RAB14 pathway. AKT1 inhibitors counteract the bacterial manipulation of host signalling processes, thus controlling intracellular growth of bacteria. By using a reciprocal chemical genetics approach, we identified kinase inhibitors with antibiotic properties and their host targets, and we determined host signalling networks that are activated by intracellular bacteria for survival.
机译:随着耐多药(MDR)细菌的出现,迫切需要开发新的干预策略。当前的抗生素通常靶向病原体而不是宿主特异性的生化途径。在这里,我们开发了激酶抑制剂,可防止无关病原体如鼠伤寒沙门氏菌和结核分枝杆菌的细胞内生长。使用自动显微镜对人肌组进行RNA干扰筛选后,发现了几种能够抑制鼠伤寒沙门氏菌细胞内生长的宿主激酶。鉴定出的激酶聚集在AKT1(也称为PKB)周围的一个网络中。 AKT1抑制剂可防止包括MDR-M在内的各种细菌的细胞内生长。结核。 AKT1由鼠伤寒沙门氏菌效应物SopB激活,后者通过控制PAK4的肌动蛋白动力学和通过AS 160(也称为TBC1D4)-RAB14途径的吞噬体-溶酶体融合来促进细胞内存活。 AKT1抑制剂可抵消细菌对宿主信号传导过程的操纵,从而控制细菌的细胞内生长。通过使用双向化学遗传学方法,我们确定了具有抗生素特性的激酶抑制剂及其宿主靶标,并确定了被细胞内细菌激活以存活的宿主信号网络。

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