title: Nizatidine and omeprazole enhance the effect of metronidazole on Helicobacter pylori in vitro.
abstract: Treatment failures are common in patients infected with metronidazole-resistant Helicobacter pylori in the gastric mucosa when triple therapy including metronidazole is used. In patients with treatment failure and metronidazole-resistant H. pylori, a higher eradication rate for H. pylori was found after secondary treatment with bismuth/ranitidine in combination with antibiotics including metronidazole, compared with the same antibiotics combined with a standard dose of omeprazole. This agrees with our previous finding that bismuth was able to reduce the susceptibility of H. pylori to metronidazole. In this study, we have found that nizatidine, an H(2)-receptor antagonist, is also able to reduce the susceptibility of H. pylori to metronidazole in vitro, despite having no direct inhibitory effect on the growth of H. pylori. This agrees with earlier findings that compounds having the ability to reverse antibiotic resistance do not necessarily have an antibiotic or chemotherapeutic effect in the sense of growth inhibition. Therefore, it was decided to investigate the effect of nizatidine and omeprazole on the oxidative respiratory chain, as it is known that metronidazole is able to inhibit the activity of fumarate reductase of H. pylori. This enzyme is a key enzyme in the alternative respiratory chain under anaerobic conditions. Nizatidine was, in these preliminary experiments, found to inhibit fumarate reductase in a dose-dependent way, like metronidazole, whereas omeprazole had almost no effect on fumarate reductase. No other significant effects on the enzymes of the respiratory chain were found. The synergistic effect of nizatidine on metronidazole resistant H. pylori strains could be explained by the effect on fumarate reductase, whereas the effect of omeprazole is different and could be an inhibition of a proton pump in H. pylori. Reversal of antimicrobial resistance with the help of different non-antibiotics seems to be possible by using quite different compounds, and is therefore to be explained by different molecular mechanisms.
authors.affiliation: Department of Clinical Microbiology, Helicobacter Laboratory, Building 9301, National University Hospital (Rigshospitalet), Tagensvej 20, DK-2200 Copenhagen, Denmark.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Bente
authors.initials: B
authors.lastname: Jensen
authors.forename: Lin
authors.initials: L
authors.lastname: Zhai
authors.forename: Hanne
authors.initials: H
authors.lastname: Colding
authors.forename: Aslaran
authors.initials: A
authors.lastname: Kharazmi
authors.forename: Jette E
authors.initials: JE
authors.lastname: Kristiansen
authors.forename: Leif P
authors.initials: LP
authors.lastname: Andersen
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004579:Electron Transport / Q000187:drug effects; D016480:Helicobacter pylori / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008795:Metronidazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D016567:Nizatidine / Q000494:pharmacology*; D009853:Omeprazole / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000897:Anti-Ulcer Agents; D008795:Metronidazole; D009853:Omeprazole; D016567:Nizatidine