title: Salicylidene acylhydrazides that affect type III protein secretion in Salmonella enterica serovar typhimurium.
abstract: A collection of nine salicylidene acylhydrazide compounds were tested for their ability to inhibit the activity of virulence-associated type III secretion systems (T3SSs) in Salmonella enterica serovar Typhimurium. The compounds strongly affected Salmonella pathogenicity island 1 (SPI1) T3SS-mediated invasion of epithelial cells and in vitro secretion of SPI1 invasion-associated effector proteins. The use of a SPI1 effector beta-lactamase fusion protein implicated intracellular entrapment of the protein construct upon application of a salicylidene acylhydrazide, whereas the use of chromosomal transcriptional gene fusions revealed a compound-mediated transcriptional silencing of SPI1. Salicylidene acylhydrazides also affected intracellular bacterial replication in murine macrophage-like cells and blocked the transport of an epitope-tagged SPI2 effector protein. Two of the compounds significantly inhibited bacterial motility and expression of extracellular flagellin. We conclude that salicylidene acylhydrazides affect bacterial T3SS activity in S. enterica and hence could be used as lead substances when designing specific inhibitors of bacterial T3SSs in order to pharmaceutically intervene with bacterial virulence.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, Stockholm, Sweden.
authors.forename: Aurel
authors.initials: A
authors.lastname: Negrea
authors.forename: Eva
authors.initials: E
authors.lastname: Bjur
authors.forename: Sofia Eriksson
authors.initials: SE
authors.lastname: Ygberg
authors.forename: Mikael
authors.initials: M
authors.lastname: Elofsson
authors.forename: Hans
authors.initials: H
authors.lastname: Wolf-Watz
authors.forename: Mikael
authors.initials: M
authors.lastname: Rhen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D004847:Epithelial Cells / Q000382:microbiology; D005407:Flagella / Q000502:physiology; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000382:microbiology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006834:Hydrazines; D008565:Membrane Proteins; C440638:SPI-2 protein, Salmonella; C419942:Spi1 protein, Salmonella