title: A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis.
abstract: The intracellular pathogen Chlamydia trachomatis possesses a type III secretion (TTS) system believed to deliver a series of effector proteins into the inclusion membrane (Inc-proteins) as well as into the host cytosol with perceived consequences for the pathogenicity of this common venereal pathogen. Recently, small molecules were shown to block the TTS system of Yersinia pseudotuberculosis. Here, we show that one of these compounds, INP0400, inhibits intracellular replication and infectivity of C. trachomatis at micromolar concentrations resulting in small inclusion bodies frequently containing only one or a few reticulate bodies (RBs). INP0400, at high concentration, given at the time of infection, partially blocked entry of elementary bodies into host cells. Early treatment inhibited the localization of the mammalian protein 14-3-3beta to the inclusions, indicative of absence of the early induced TTS effector IncG from the inclusion membrane. Treatment with INP0400 during chlamydial mid-cycle prevented secretion of the TTS effector IncA and homotypic vesicular fusions mediated by this protein. INP0400 given during the late phase resulted in the detachment of RBs from the inclusion membrane concomitant with an inhibition of RB to elementary body conversion causing a marked decrease in infectivity.
authors.affiliation: Swedish Institute for Infectious Disease Control, Nobels väg 18, SE-171 82 Solna, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Muschiol
authors.forename: Leslie
authors.initials: L
authors.lastname: Bailey
authors.forename: Asa
authors.initials: A
authors.lastname: Gylfe
authors.forename: Charlotta
authors.initials: C
authors.lastname: Sundin
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.forename: Sven
authors.initials: S
authors.lastname: Bergström
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
authors.forename: Hans
authors.initials: H
authors.lastname: Wolf-Watz
authors.forename: Staffan
authors.initials: S
authors.lastname: Normark
authors.forename: Birgitta
authors.initials: B
authors.lastname: Henriques-Normark
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D002690:Chlamydia Infections / Q000188:drug therapy*; D002692:Chlamydia trachomatis / Q000166:cytology / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D002479:Inclusion Bodies / Q000648:ultrastructure; D008561:Membrane Fusion; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport
chemical_list: D048948:14-3-3 Proteins; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C094163:IncA protein, bacteria; D010750:Phosphoproteins