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Antimicrobial Agents and Chemotherapy, August 2007, p. 2867-2876, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00223-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Salicylidene Acylhydrazides That Affect Type III Protein Secretion in Salmonella enterica Serovar Typhimurium

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, 171 77 Stockholm, Sweden,¹ The Swedish Institute for Infectious Disease Control, Nobels väg 18, 171 82 Solna, Sweden,² Organic Chemistry, Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden,³ Department of Molecular Biology, Umeå University, SE-90187 Umeå, Sweden⁴

Received 14 February 2007/ Returned for modification 19 April 2007/ Accepted 26 May 2007

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 ß-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.

Published ahead of print on 4 June 2007.