A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis

• 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.

Nyckelord

14-3-3 Proteins/metabolism

Anti-Bacterial Agents/chemistry/*pharmacology

Bacterial Proteins/*antagonists & inhibitors/metabolism

Cell Differentiation

Cell Membrane/metabolism

Chlamydia Infections/*drug therapy

Chlamydia trachomatis/cytology/*drug effects/*physiology/ultrastructure

Dose-Response Relationship; Drug

Inclusion Bodies/ultrastructure

Membrane Fusion

Phosphoproteins/metabolism

Protein Binding

Protein Transport

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