title: Integrating chemical and genetic silencing strategies to identify host kinase-phosphatase inhibitor networks that control bacterial infection.
abstract: 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 including 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.
authors.affiliation: Division of Cell Biology, ‡Netherlands Proteomics Centre, and §Division of Biochemistry, The Netherlands Cancer Institute , Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Harald M H G
authors.initials: HM
authors.lastname: Albers
authors.forename: Coenraad
authors.initials: C
authors.lastname: Kuijl
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bakker
authors.forename: Loes
authors.initials: L
authors.lastname: Hendrickx
authors.forename: Sharida
authors.initials: S
authors.lastname: Wekker
authors.forename: Nadha
authors.initials: N
authors.lastname: Farhou
authors.forename: Nora
authors.initials: N
authors.lastname: Liu
authors.forename: Bernat
authors.initials: B
authors.lastname: Blasco-Moreno
authors.forename: Tiziana
authors.initials: T
authors.lastname: Scanu
authors.forename: Jeroen
authors.initials: J
authors.lastname: den Hertog
authors.forename: Patrick
authors.initials: P
authors.lastname: Celie
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D020868:Gene Silencing; D054884:Host-Pathogen Interactions; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012480:Salmonella Infections / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D012486:Salmonella typhimurium / Q000187:drug effects / Q000502:physiology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D051057:Proto-Oncogene Proteins c-akt; D054637:Dual-Specificity Phosphatases