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Inhibitors of Helicobacter pylori ATPase Cagα block CagA transport and cag virulence

Authors :
Paolo Ruggiero
Claudia Gianfaldoni
Markus Hilleringmann
Michael Doyle
Mary Lee MacKichan
Werner Pansegrau
Susan Kaufman
Antonello Covacci
Source :
Microbiology. 152:2919-2930
Publication Year :
2006
Publisher :
Microbiology Society, 2006.

Abstract

With the steadily increasing occurrence of antibiotic resistance in bacteria, there is a great need for new antibacterial compounds. The approach described here involves targeting virulence-related bacterial type IV secretion systems (TFSSs) with small-molecule inhibitors. The cag TFSS of Helicobacter pylori was chosen as a model, and novel inhibitors directed against the cag VirB11-type ATPase Cagα were identified. The cag genes encode proteins that are components of a contact-dependent secretion system used by the bacterium to translocate the effector molecule CagA into host cells. Translocated CagA is associated with severe gastritis, and carcinoma. Furthermore, functional TFSSs and immunodominant CagA play a role in interleukin (IL)-8 induction, which is an important factor for chronic inflammation. Inhibitors of Cagα were identified by high-throughput screening of chemical libraries that comprised 524 400 small molecules. The ATPase activity of Cagα was inhibited by the selected compounds in an in vitro enzymic assay using the purified enzyme. The most active compound, CHIR-1, reduced TFSS function to an extent that cellular effects on AGS cells mediated by CagA were virtually undetectable, while reduced levels of IL-8 induction were observed. Gastric colonization by CHIR-1-pre-treated bacteria was found to be impaired in a dose-dependent manner using a mouse model of infection. Small-molecule Cagα inhibitors, the first described inhibitors of a TFSS, are potential candidates for the development of new antibacterial compounds that may lead to alternative medical treatments. The compounds are expected to impose weak selective pressure, since they target virulence functions. Moreover, the targeted virulence protein is conserved in a variety of bacterial pathogens. Additionally, TFSS inhibitors are potent tools to study the biology of TFSSs.

Details

ISSN :
14652080 and 13500872
Volume :
152
Database :
OpenAIRE
Journal :
Microbiology
Accession number :
edsair.doi.dedup.....4ae78c563bbbbe7445996897c3eb753c
Full Text :
https://doi.org/10.1099/mic.0.28984-0