Novel compounds targeting the enterohemorrhagic Escherichia coli type three secretion system reveal insights into mechanisms of secretion inhibition

Riccardo Zambelloni, James P R Connolly, Alejandro Huerta Uribe, Karl Burgess, Rodolfo Marquez, Andrew J Roe

Research output: Contribution to journalArticlepeer-review

Abstract

Anti-virulence (AV) compounds are a promising alternative to traditional antibiotics for fighting bacterial infections. The Type Three Secretion System (T3SS) is a well-studied and attractive AV target, given that it is widespread in more than 25 species of Gram-negative bacteria, including enterohaemorrhagic E. coli (EHEC), and since it is essential for host colonisation by many pathogens. In this work, we designed, synthesized and tested a new series of compounds that block the functionality of the T3SS of EHEC. Affinity chromatography experiments identified the primary target of the compounds as the T3SS needle pore protein EspD, which is essential for effector protein translocation into host cells. These data were supported by mechanistic studies that determined the coiled-coil domain 1 of EspD as a key compound-binding site, thereby preventing correct assembly of the T3SS complex on the cell surface. However, binding of inhibitors to EspD or deletion of EspD itself did not result in transcriptional down-regulation of effector proteins. Instead, we found the compounds to exhibit dual-functionality by also down-regulating transcription of the entire chromosomal locus encoding the T3SS, further demonstrating their desirability and effectiveness. This article is protected by copyright. All rights reserved.

Original languageEnglish
Pages (from-to)606-619
Number of pages14
JournalMolecular Microbiology
Volume105
Issue number4
Early online date14 Jun 2017
DOIs
Publication statusPublished - 1 Aug 2017

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