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

Zambelloni, R., Connolly, J. P.R., Huerta Uribe, A., Burgess, K., Marquez, R. and Roe, A. J. (2017) Novel compounds targeting the enterohemorrhagic Escherichia coli type three secretion system reveal insights into mechanisms of secretion inhibition. Molecular Microbiology, 105(4), pp. 606-619. (doi:10.1111/mmi.13719) (PMID:28557017) (PMCID:PMC5575525)

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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 enterohemorrhagic E. coli (EHEC), and as it is essential for host colonization 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Roe, Professor Andrew and Burgess, Dr Karl and Connolly, Dr James and Zambelloni, Riccardo and Huerta Uribe, Alejandro
Authors: Zambelloni, R., Connolly, J. P.R., Huerta Uribe, A., Burgess, K., Marquez, R., and Roe, A. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Molecular Microbiology
Publisher:Wiley
ISSN:0950-382X
ISSN (Online):1365-2958
Published Online:14 June 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Molecular Microbiology 105(4):606-619
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
691101Where and Why: The Influence of Host Metabolism on Bacterial Niche SpecificityAndrew RoeBiotechnology and Biological Sciences Research Council (BBSRC)BB/M029646/1III - BACTERIOLOGY
576661Identification of astrocytic factors that regulate myelinationSusan BarnettWellcome Trust (WELLCOTR)089891/Z/09/ZIII -IMMUNOLOGY