title: Treatment of Chlamydia trachomatis with a small molecule inhibitor of the Yersinia type III secretion system disrupts progression of the chlamydial developmental cycle.
abstract: The obligate intracellular bacterium Chlamydia trachomatis possesses a biphasic developmental cycle that is manifested by differentiation of infectious, metabolically inert elementary bodies (EBs) to larger, metabolically active reticulate bodies (RBs). The cycle is completed by asynchronous differentiation of dividing RBs back to a population of dormant EBs that can initiate further rounds of infection upon lysis of the host cell. Chlamydiae express a type III secretion system (T3SS) that is presumably employed to establish and maintain the permissive intracellular niche by secretion of anti-host proteins. We hypothesize that T3SS activity is essential for chlamydial development and pathogenesis. However, the lack of a genetic system has confounded efforts to establish any role of the T3SS. We therefore employed the small molecule Yersinia T3SS inhibitor N'-(3,5-dibromo-2-hydroxybenzylidene)-4-nitrobenzohydrazide, designated compound 1 (C1), to examine the interdependence of the chlamydial T3SS and development. C1 treatment inhibited C. trachomatis but not T4SS-expressing Coxiella burnetii development in a dose-dependent manner. Although chlamydiae remained viable and metabolically active, they failed to divide significantly and RB to EB differentiation was inhibited. These effects occurred in the absence of host cell cytotoxicity and were reversible by washing out C1. We further demonstrate that secretion of T3S substrates is perturbed in C1-treated chlamydial cultures. We have therefore provided evidence that C1 can inhibit C. trachomatis development and T3SS activity and present a model in which progression of the C. trachomatis developmental cycle requires a fully functional T3SS.
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wolf
authors.forename: H J
authors.initials: HJ
authors.lastname: Betts
authors.forename: B
authors.initials: B
authors.lastname: Chellas-Géry
authors.forename: S
authors.initials: S
authors.lastname: Hower
authors.forename: C N
authors.initials: CN
authors.lastname: Linton
authors.forename: K A
authors.initials: KA
authors.lastname: Fields
mesh_terms: D001426:Bacterial Proteins / Q000032:analysis / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000032:analysis / Q000378:metabolism; D002692:Chlamydia trachomatis / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D016997:Coxiella burnetii / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D015007:Yersinia / Q000187:drug effects / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D018834:Chaperonin 60; D006834:Hydrazines; C460868:IncA protein, Chlamydia trachomatis; D008565:Membrane Proteins; C515036:N'-(3,5-dibromo-2-hydroxybenzylidene)-4-nitrobenzohydrazide