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: | Connolly, Dr James and Roe, Professor Andrew and Huerta Uribe, Mr Alejandro and Burgess, Dr Karl and Zambelloni, Riccardo |
| 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 > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| 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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