Abstract
Helicobacter pylori (H. pylori) produces urease in order to improve its settlement and growth in the human gastric epithelium. Urease inhibitors likely represent potentially powerful therapeutics for treating H. pylori; however, their instability and toxicity have proven problematic in human clinical trials. In this study, we investigate the ability of a natural compound extracted from Zingiber zerumbet Smith, zerumbone, to inhibit the urease activity of H. pylori by formation of urease dimers, trimers, or tetramers. As an oxygen atom possesses stronger electronegativity than the first carbon atom bonded to it, in the zerumbone structure, the neighboring second carbon atom shows a relatively negative charge (δ−) and the next carbon atom shows a positive charge (δ+), sequentially. Due to this electrical gradient, it is possible that H. pylori urease with its negative charges (such as thiol radicals) might bind to the β-position carbon of zerumbone. Our results show that zerumbone dimerized, trimerized, or tetramerized with both H. pylori urease A and urease B molecules, and that this formation of complex inhibited H. pylori urease activity. Although zerumbone did not affect either gene transcription or the protein expression of urease A and urease B, our study demonstrated that zerumbone could effectively dimerize with both urease molecules and caused significant functional inhibition of urease activity. In short, our findings suggest that zerumbone may be an effective H. pylori urease inhibitor that may be suitable for therapeutic use in humans.
Highlights
According to the WHO in 2018, gastric cancer is the fifth most common malignancy worldwide and the third leading cause of cancer-related morbidity [1]
We determined the concentration of zerumbone below the minimal inhibitory concentration (MIC) appropriate to measure urease activity through repeated preliminary experiments; 20 μM of condition to the maximum
H. pylori produces an abundant amount of urease in order to neutralize the acidic gastric environment via the hydrolysis of urea into ammonia and carbon dioxide [6]
Summary
According to the WHO in 2018, gastric cancer is the fifth most common malignancy worldwide and the third leading cause of cancer-related morbidity [1]. Among certain factors responsible for the high gastric cancer rate, Helicobacter pylori (H. pylori) infection is a common cause and prevalent in East-Asian countries, including South Korea, Japan and China [2]. To eradicate H. pylori infection in South Korea, physicians have adopted a standard triple therapy that typically includes one proton-pump inhibitor (PPI) and two antimicrobial agents administered over the course of 10–14 days [3,4]. Antibiotic resistance has become more prevalent over time and has resulted in a failure to eradicate H. pylori in South Korea. H. pylori urease exists as a heterodimer of the structural subunits urease A (UreA) and urease B (UreB), which are arranged in a dodecameric ((AB)3) structure with two nickel ions (Ni2+) bound by each urease dimer [7]. H. pylori can survive in hostile pH conditions due to its abundant secretion of urease, and despite not being an acidophile [6], can reach and colonize the gastric mucosa in humans [10]
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