title: The effect of the potential PhoQ histidine kinase inhibitors on Shigella flexneri virulence.
abstract: PhoQ/PhoP is an important two-component system that regulates Shigella virulence. We explored whether the PhoQ/PhoP system is a promising target for new antibiotics against S. flexneri infection. By using a high-throughput screen and enzymatic activity coupled assay, four compounds were found as potential PhoQ inhibitors. These compounds not only inhibited the activity of SF-PhoQc autophosphorylation but also displayed high binding affinities to the SF-PhoQc protein in the Surface Plasmon Resonance response. A S. flexneri cell invasion assay showed that three of these potential PhoQ inhibitors inhibit the invasion of HeLa cells by S. flexneri 9380. In a Mouse Sereny test, mice inoculated with S. flexneri 9380 pre-treated with the potential PhoQ inhibitors 1, 2, 3 or 4 displayed no inflammation, whereas mice inoculated with S. flexneri 9380 alone displayed severe keratoconjunctival inflammation. All four potential PhoQ inhibitors showed no significant cytotoxicity or hemolytic activity. These data suggest that the four potential PhoQ inhibitors inhibited the virulence of S. flexneri and that PhoQ/PhoP is a promising target for the development of drugs against S. flexneri infection.
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institute of Medical Microbiology, Fudan University, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Cai
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Mingliang
authors.initials: M
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.forename: Jiayu
authors.initials: J
authors.lastname: Chen
authors.forename: Junqin
authors.initials: J
authors.lastname: Zhang
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Di
authors.initials: D
authors.lastname: Qu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects; D019295:Computational Biology; D004912:Erythrocytes / Q000187:drug effects; D006367:HeLa Cells; D006461:Hemolysis / Q000187:drug effects; D000071677:Histidine Kinase; D006801:Humans; D007637:Keratoconjunctivitis / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects / Q000472:pathogenicity; D020539:Sequence Analysis, Protein; D012763:Shigella flexneri / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity*; D014774:Virulence / Q000187:drug effects
chemical_list: D001426:Bacterial Proteins; C079792:PhoQ protein, Bacteria; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D000071677:Histidine Kinase