Pyruvate decarboxylase, the target for omeprazole in metronidazole-resistant and iron-restricted Tritrichomonas foetus.
The substituted benzimidazole omeprazole, used for the treatment of human peptic ulcer disease, inhibits the growth of the metronidazole-resistant bovine pathogen Tritrichomonas foetus in vitro (MIC at which the growth of parasite cultures is inhibited by 50%, 22 microg/ml [63 microM]). The antitrichomonad activity appears to be due to the inhibition of pyruvate decarboxylase (PDC), which is the key enzyme responsible for ethanol production and which is strongly upregulated in metronidazole-resistant trichomonads. PDC was purified to homogeneity from the cytosol of metronidazole-resistant strain. The tetrameric enzyme of 60-kDa subunits is inhibited by omeprazole (50% inhibitory concentration, 16 microg/ml). Metronidazole-susceptible T. foetus, which expresses very little PDC, is only slightly affected. Omeprazole has the same inhibitory effect on T. foetus cells grown under iron-limited conditions. Similarly to metronidazole-resistant cells, T. foetus cells grown under iron-limited conditions have nonfunctional hydrogenosomal metabolism and rely on cytosolic PDC-mediated ethanol fermentation.
Sutak
Róbert
R
Department of Parasitology, Charles University, Vinicná 7, 128 44 Prague 2, Czech Republic.
Tachezy
Jan
J
Kulda
Jaroslav
J
Hrdý
Ivan
I
D000818:Animals; D000994:Antitrichomonal Agents / Q000494:pharmacology*; D015153:Blotting, Western; D004351:Drug Resistance; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000090463:Iron Deficiencies; D007700:Kinetics; D008795:Metronidazole / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009853:Omeprazole / Q000494:pharmacology*; D011767:Pyruvate Decarboxylase / Q000187:drug effects*; D016835:Tritrichomonas foetus / Q000187:drug effects*
D000994:Antitrichomonal Agents; D004791:Enzyme Inhibitors; D008795:Metronidazole; D011767:Pyruvate Decarboxylase; D009853:Omeprazole