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

Ewa Grave,Michiro Otaka,Nobuaki Ogawa,Takako Ohtaki-Mizoguchi,Keiji Oguma,Soh Yamamoto,Tomoya Okamoto,Kenji Yokota,Shin-Ichi Yokota,Hideaki Itoh,Arisa Tamura,Kazuhiko Fujiwara

doi:10.1038/srep13738

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.

Highlights

The microaerophilic gram-negative bacterium Helicobacter pylori can colonize the human stomach
We have previously reported that HSC70 and HSP70 bind to a GGA-affinity matrix[24]
We investigated the properties of binding of GGA to both H. pylori and human HSP70, and the effect of GGA on H. pylori cells

Summary

Introduction

The microaerophilic gram-negative bacterium Helicobacter pylori can colonize the human stomach. The first-line eradication regimen is a three-drug combination therapy using a proton pump inhibitor (such as lansoprazole, omeprazole, rabeprazole, or esomeprazole), amoxicillin, and clarithromycin. Failures of this treatment have increased, because of the appearance of antibiotic-resistant (especially clarithromycin) H. pylori. GGA is shown to suppress H. pylori- induced tissue and cell injury[7,8] and inflammatory reaction[9,10], so it is expected to show beneficial effects on H. pylori-infected tissues. HSP70s are present in mammalian cells as two different gene products that are closely related: a stress-inducible form, HSP70 (known as HSP72), and a constitutively expressed form, HSC70 (known as HSP73)[17]. The released HSF-1 is phosphorylated and activated, acquiring the ability to bind to a heat shock element (HSE) in the promoter of the heat-inducible HSP70 gene and resulting in induction of HSP70 expression

Methods

Results

Conclusion