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. 2004 Jun;48(6):2185-9.
doi: 10.1128/AAC.48.6.2185-2189.2004.

Pyruvate decarboxylase, the target for omeprazole in metronidazole-resistant and iron-restricted Tritrichomonas foetus

Róbert Sutak  1 , Jan Tachezy, Jaroslav Kulda, Ivan Hrdý
Affiliations

Pyruvate decarboxylase, the target for omeprazole in metronidazole-resistant and iron-restricted Tritrichomonas foetus

Róbert Sutak et al. Antimicrob Agents Chemother. 2004 Jun.

Abstract

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.

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Figures

FIG. 1.
FIG. 1.
Structures of thiamine (a), omeprazole (b), and metronidazole (c).
FIG. 2.
FIG. 2.
(A) SDS-PAGE of PDC fractions during purification steps from metronidazole-resistant T. foetus cytosol. Lanes: 1, molecular weight standards; 2, cytosol; 3, fractions after butyl HIC column chromatography; 4, fractions obtained after hydroxyapatite column chromatography; 5, fractions obtained after UNO Q 1 column chromatography; 6, fractions obtained after Bio-Prep 1000 column chromatography. Proteins were stained with Coomassie brilliant blue. (B) Immunodetection of PDC in the cytosolic fractions of T. foetus. Lanes: 1, metronidazole-resistant strain; 2, metronidazole-sensitive strain; 3, metronidazole-sensitive strain grown under iron-limited conditions.
FIG. 3.
FIG. 3.
Effect of omeprazole on activity of purified PDC from metronidazole-resistant T. foetus. The data represent the means ± standard deviations of five measurements.
See this image and copyright information in PMC

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