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Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology.

ABSTRACT: Geranylgeranylacetone (GGA) is used to treat patients suffering from peptic ulcers and gastritis. We examined the effect of GGA on Helicobacter pylori, which is a causative factor of gastrointestinal diseases. Previously, we have reported that GGA binds specifically to the molecular chaperone HSP70. In this paper, we report that GGA bounds to H. pylori HSP70 (product of the DnaK gene) with 26-times higher affinity than to human HSP70, and induced large conformational changes as observed from surface plasmon resonance and circular dichroism. Binding of GGA suppressed the activity of the H. pylori chaperone. GGA also altered several characteristics of H. pylori cells. GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells. GGA also caused morphological alterations in H. pylori as reflected in fewer coccoid-like cells, suggesting that GGA converts H. pylori to an actively dividing, spiral state (vegetative form) from a non-growing, coccoid state. This morphological conversion by GGA resulted in accelerated growth of H. pylori. These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

SUBMITTER: Grave E

PROVIDER: S-EPMC4561889 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology.

Grave Ewa E Yokota Shin-ichi S Yamamoto Soh S Tamura Arisa A Ohtaki-Mizoguchi Takako T Yokota Kenji K Oguma Keiji K Fujiwara Kazuhiko K Ogawa Nobuaki N Okamoto Tomoya T Otaka Michiro M Itoh Hideaki H

Scientific reports 20150908

Geranylgeranylacetone (GGA) is used to treat patients suffering from peptic ulcers and gastritis. We examined the effect of GGA on Helicobacter pylori, which is a causative factor of gastrointestinal diseases. Previously, we have reported that GGA binds specifically to the molecular chaperone HSP70. In this paper, we report that GGA bounds to H. pylori HSP70 (product of the DnaK gene) with 26-times higher affinity than to human HSP70, and induced large conformational changes as observed from sur ...[more]

PMID: 26345206

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Project description:The primary mode of transmission of Helicobacter pylori, a human pathogen carried by more than half the population worldwide, is still unresolved. Some epidemiological data suggest water as a possible transmission route. H. pylori in the environment transforms into a nonculturable, coccoid form, which frequently results in the failure to detect this bacterium in environmental samples by conventional culture techniques. To overcome limitations associated with culturing, molecular approaches based on DNA amplification by PCR have been developed and used for the detection of H. pylori in clinical and environmental samples. Our results showed the glmM gene as the most promising target for detection of H. pylori by PCR amplification. Under optimal amplification conditions, glmM-specific primers generated PCR-amplified products that were specific for H. pylori and some other Helicobacter species. Genome sequence analysis revealed the existence of a conserved region linked to a hypervariable region upstream of the 16S rRNA gene of H. pylori. Selective PCR primer sets targeting this sequence were evaluated for the specific detection of H. pylori. One primer set, Cluster2 and B1J99, were shown to be highly specific for H. pylori strains and did not produce any PCR products when other Helicobacter species and other bacterial species were analyzed. In tests with 32 strains of H. pylori, 6 strains of other Helicobacter species, 8 strains of Campylobacter jejuni, and 21 strains belonging to different genera, the primers for glmM were selective for the Helicobacter genus and the primers containing the region flanking the 16S rRNA gene were selective for H. pylori species only. The combination of two sensitive PCR-based methods, one targeting the glmM gene and the other targeting a hypervariable flanking region upstream of the 16S rRNA gene, are complementary to each other. Whereas the glmM-specific primers provide a rapid, sensitive presumptive assay for the presence of H. pylori and closely related Helicobacter spp., the primers for sequences flanking the 16S rRNA gene can confirm the presence of H. pylori and locate the potential source of this bacterium.

Project description:ObjectiveInfection with Helicobacter pylori (H pylori), especially cytotoxin-associated gene A-positive (CagA+) strains, has been associated with various gastrointestinal and extragastric diseases. The aim of this study was to characterize H pylori-induced alterations in the gastric and tongue coating microbiota and evaluate their potential impacts on human health.DesignThe gastric mucosa and tongue coating specimens were collected from 80 patients with chronic gastritis, and microbiota profiles were generated by 16S rRNA gene sequencing. Samples were grouped as H pylori negative (n = 32), CagA-negative H pylori infection (n = 13), and CagA-positive H pylori infection (n=35). The comparison of bacterial relative abundance was made using a generalized linear model. Functional profiling of microbial communities was predicted with PICRUSt and BugBase. Microbial correlation networks were produced by utilizing SparCC method.ResultsSignificant alterations of the gastric microbiota were found in the H pylori+/CagA+ samples, represented by a decrease in bacterial diversity, a reduced abundance of Roseburia, and increased abundances of Helicobacter and Haemophilus genera. At the community level, functions involved in biofilm forming, mobile element content, and facultative anaerobiosis were significantly decreased in gastric microbiome of the H pylori+ subjects. The presence of CagA gene was linked to an increased proportion of Gram-negative bacteria in the stomach, thereby contributing to an upregulation of lipopolysaccharide (LPS) biosynthesis. The number of bacterial interactions was greatly reduced in networks of both tongue coating and gastric microbiota of the H pylori+/CagA+ subject, and the cooperative bacterial interactions dominated the tongue coating microbiome.ConclusionsInfection with H pylori strains possessing CagA may increase the risk of various diseases, by upregulating LPS biosynthesis in the stomach and weakening the defense of oral microbiota against microorganisms with pathogenic potential.

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Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology.

Publications

Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology.

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