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Inhibitors of Helicobacter pylori ATPase Cagα block CagA transport and cag virulence
- 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.
- Subjects :
- ATPase
Colony Count, Microbial
Drug Evaluation, Preclinical
Virulence
Microbiology
Helicobacter Infections
Mice
Bacterial Proteins
Cell Line, Tumor
Animals
Humans
CagA
Secretion
Enzyme Inhibitors
Adenosine Triphosphatases
chemistry.chemical_classification
Antigens, Bacterial
Microscopy, Confocal
Helicobacter pylori
biology
Effector
Interleukin-8
Epithelial Cells
biology.organism_classification
In vitro
Anti-Bacterial Agents
Enzyme
Microscopy, Fluorescence
chemistry
Gastric Mucosa
biology.protein
Subjects
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