Potential of fumarate reductase as a novel therapeutic target in Helicobacter pylori infection

Abstract

Approximately 50% of the world's population carries Helicobacter pylori, a gastric bacterial pathogen linked to diseases including gastritis, ulcers and gastric cancer. Chemotherapies are being routinely used to treat systemic H. pylori infection. The common regimens consist of proton pump inhibitors (PPIs) or ranitidine bismuth citrate (RBC) and two antibiotics. Although these regimens efficiently eradicate H. pylori, the emergence of antibiotic-resistant H. pylori strains, their severe side effects and high costs are major drawbacks of these treatments. More efficient, economic and friendly drugs need to be developed. Fumarate reductase (FRD) catalyses the reduction of fumarate to succinate in the Krebs cycle and is also a key enzyme in anaerobic respiration with fumarate as the terminal electron acceptor for many facultative bacteria. H. pylori FRD contains three subunits, FrdA, FrdB and FrdC. Genome analysis and experimental evidence indicate that this enzyme appears to play an important role in the energy metabolism of H. pylori. In addition, FRD is essential for the colonisation of H. pylori in the acidic stomach as demonstrated in the mouse model of infection. Furthermore, three FRD inhibitors used to cure helminthic infection in animals and humans have both inhibitory and bactericidal effects on H. pylori. These lines of evidence indicate that FRD may be a promising chemotherapeutic target. Given that FrdA is strongly immunogenic in the sera from H. pylori-positive patients, this protein may also be used as a candidate for the development of an anti-H. pylori vaccine.

The Dual-Functioning Fumarate Reductase Is the Sole Succinate:Quinone Reductase in Campylobacter jejuni and Is Required for Full Host Colonization

“…The fumarate reductase of H. pylori is required for colonization of mice (8) and has been studied as a potential drug target (7,24). The ability of an E. coli fumarate reductase mutant to colonize mice also was significantly decreased (13).…”

The Real Fact in Irritable Bowel Syndrome

“…This suggestion is supported by the fact that the major routes of generation of energy for H. pylori are via pyruvate and the activity of the pyruvate dehydrogenase complex is controlled by the rules of product inhibition and feedback regulation. It is further supported by the observation that addition of pyruvate to different solid culture media was found to inhibit bacterial growth, and this inhibition was attributed to accumulation of acetate and formate [11][12][13]. As the matter includes interference with the energy metabolism and the respiratory chain of H. pylori; an immediate paralysis of the bacterium can be considered with dramatic relief of patient's symptoms.…”

“…The complex nutritional requirements of H. pylori are achieved through its unique energy metabolism, which exhibits characteristic dislocation sites. These sites can be considered as targets that should attract any attempts to fight the organism [12]. As acetate is demonstrated as an end product among the metabolic pathway of H. pylori; this means that addition of acetic acid in the atmosphere around H. pylori could compromise the energy metabolism of H. pylori, or interfere with the organism's respiratory chain metabolism.…”

The Dramatic Spread of Diabetes Mellitus Worldwide and Influence of Helicobacter pylori

“…The complex nutritional requirements of H. pylori are achieved mainly via utilization of pyruvate. As acetate is demonstrated as an end product among the metabolic pathway of H. pylori and the activity of the pyruvate dehydrogenase complex is controlled by the rules of product inhibition and feedback regulation; this means that addition of acetic acid to the medium could compromise the energy metabolism of H. pylori, or interfere with the organism's respiratory chain metabolism [22][23][24][25][26].…”