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

Lookup NU author(s): James Connolly

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2017 The Authors. Molecular Microbiology Published by John Wiley & Sons Ltd. 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.


Publication metadata

Author(s): Zambelloni R, Connolly JPR, Huerta Uribe A, Burgess K, Marquez R, Roe AJ

Publication type: Article

Publication status: Published

Journal: Molecular Microbiology

Year: 2017

Volume: 105

Issue: 4

Pages: 606-619

Print publication date: 01/08/2017

Online publication date: 14/06/2017

Acceptance date: 02/04/2016

Date deposited: 20/09/2019

ISSN (print): 0950-382X

ISSN (electronic): 1365-2958

Publisher: Wiley-Blackwell

URL: https://doi.org/10.1111/mmi.13719

DOI: 10.1111/mmi.13719

PubMed id: 28557017


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