Potential of fumarate reductase as a novel therapeutic target in Helicobacter pylori infection.
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.
Ge
Zhongming
Z
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, 16-873, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. zge@mit.edu
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000907:Antibodies, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D001428:Bacterial Vaccines; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005756:Gastritis / Q000188:drug therapy*; D016481:Helicobacter Infections / Q000188:drug therapy*; D016480:Helicobacter pylori / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D006801:Humans; D051379:Mice; D021122:Protein Subunits; D013385:Succinate Dehydrogenase / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology
D000871:Anthelmintics; D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D004791:Enzyme Inhibitors; D021122:Protein Subunits; D013385:Succinate Dehydrogenase