Integrating Chemical and Genetic Silencing Strategies To Identify Host Kinase-Phosphatase Inhibitor Networks That Control Bacterial Infection
Integrating Chemical and Genetic Silencing Strategies To Identify Host Kinase-Phosphatase Inhibitor Networks That Control Bacterial Infection
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DOI：
10.1021/cb400421a
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发表时间：
2014-02-01
影响因子：
4
通讯作者：
Neefjes, Jacques
中科院分区：
文献类型：
--
作者：
Abers, Harald M. H. G.;Kuijl, Coenraad;Neefjes, Jacques
每年有300万人死于细菌感染，由于对当前抗生素的耐药性，这一数字可能会进一步增加。这些抗生素靶向几乎所有基本的细菌过程，只留下一些新的目标进行操作。为了控制细菌感染，宿主蛋白质组具有更多潜在的操纵靶标，如通过观察到抑制宿主激酶Akt支持消除不同的细胞内细菌（包括沙门氏菌和M.在结核病中，如果宿主激酶参与控制细菌感染，那么磷酸酶也可以。在这里，我们提出了一个集成的小干扰RNA和小分子筛选，以确定主机磷酸酶抑制剂的组合，控制细菌感染。我们定义宿主磷酸酶抑制沙门氏菌的细胞内生长，并确定相应的抑制剂的双特异性磷酸酶DUSP11和27。途径分析将控制细菌感染的许多激酶和磷酸酶置于以Akt为中心的整合途径中。该网络控制宿主细胞代谢、存活和生长以及细菌存活，并反映宿主细胞对细菌感染的天然反应。抑制两种活性相反的酶激酶和磷酸酶可能是克服耐药细菌感染的新策略。
Every year three million people die as a result of bacterial infections, and this number may further increase due to resistance to current antibiotics. These antibiotics target almost all essential bacterial processes, leaving only a few new targets for manipulation. The host proteome has many more potential targets for manipulation in order to control bacterial infection, as exemplified by the observation that inhibiting the host kinase Akt supports the elimination of different intracellular bacteria induding Salmonella and M. tuberculosis, if host kinases are involved in the control of bacterial infections, phosphatases could be as well. Here we present an integrated small interference RNA and small molecule screen to identify host phosphatase-inhibitor combinations that control bacterial infection. We define host phosphatases inhibiting intracellular growth of Salmonella and identify corresponding inhibitors for the dual specificity phosphatases DUSP11 and 27. Pathway analysis places many kinases and phosphatases controlling bacterial infection in an integrated pathway centered around Akt. This network controls host cell metabolism, survival, and growth and bacterial survival and reflect a natural host cell response to bacterial infection. Inhibiting two enzyme classes with opposite activities-kinases and phosphatases-may be a new strategy to overcome infections by antibiotic-resistant bacteria.