Novel compounds targeting the enterohemorrhagic Escherichia coli type three secretion system reveal insights into mechanisms of secretion inhibition. Issue 4 (14th June 2017)

• Record Type: Journal Article
• Authors: Zambelloni, Riccardo; Connolly, James P.R.; Huerta Uribe, Alejandro; Burgess, Karl; Marquez, Rodolfo; Roe, Andrew J.
• Is Part Of: Molecular microbiology. Volume 105:Issue 4(2017)
• Page Start: 606
• Page End: 619
• Publication Date: 2017-06-14
• Subjects: Molecular microbiology -- Periodicals; 572.829
• DOI: 10.1111/mmi.13719
• Languages: English
• ISSNs: 0950-382X

Abstract

Summary: 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. Abstract : Anti‐virulence (AV) compounds are a promising alternative to traditional antibiotics for fighting bacterial infections. In this work, we designed, synthesized and tested a new series of compounds that block the secretion system used to cause disease by some species of Escherichia coli .