Fumarate reductase: a target for therapeutic intervention against Helicobacter pylori.
The potential of fumarate reductase as a therapeutic target against the human pathogen Helicobacter pylori was investigated by studying the cytotoxicity of morantel, oxantel, and thiabendazole, known to inhibit the enzyme in parasitic worms. Nuclear magnetic resonance spectroscopy was employed to investigate the effects of the inhibitors on the fumarate reductase activity of laboratory-adapted and wild-type bacterial strains. Production of succinate from fumarate in H. pylori cells was inhibited by morantel, oxantel, and thiabendazole. Cell growth and viability techniques were used to examine the bacteriostatic and bactericidal effects of the three anthelmintics. Each of the antiparasites arrested growth and produced cell death in liquid cultures, although the minimal inhibitory and bactericidal concentrations of these compounds are such that they would not be of therapeutic use. The strength of the effects as measured by minimal inhibitory and bactericidal concentrations was oxantel > thiabendazole > morantel. The findings suggested that fumarate reductase is an essential component of the metabolism of H. pylori and as such constitutes a possible target for therapeutic intervention in the treatment of the bacterium.
Mendz
G L
GL
School of Biochemistry and Molecular Genetics, University of New South Wales, Sydney, Australia.
Hazell
S L
SL
Srinivasan
S
S
D000154:Aconitate Hydratase / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000633:toxicity; D005649:Fumarate Hydratase / Q000378:metabolism; D016481:Helicobacter Infections / Q000188:drug therapy*; D016480:Helicobacter pylori / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006801:Humans; D007700:Kinetics; D008291:Malate Dehydrogenase / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009015:Morantel / Q000627:therapeutic use / Q000633:toxicity*; D011715:Pyrantel / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*; D013827:Thiabendazole / Q000627:therapeutic use / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D011715:Pyrantel; D009015:Morantel; C003407:oxantel; D008291:Malate Dehydrogenase; D013385:Succinate Dehydrogenase; D005649:Fumarate Hydratase; D000154:Aconitate Hydratase; D013827:Thiabendazole