title: Trichomonas vaginalis flavin reductase 1 and its role in metronidazole resistance.
abstract: The enzyme flavin reductase 1 (FR1) from Trichomonas vaginalis, formerly known as NADPH oxidase, was isolated and identified. Flavin reductase is part of the antioxidative defence in T. vaginalis and indirectly reduces molecular oxygen to hydrogen peroxide via free flavins. Importantly, a reduced or absent flavin reductase activity has been reported in metronidazole-resistant T. vaginalis, resulting in elevated intracellular oxygen levels and futile cycling of metronidazole. Interestingly, FR1 has no close homologue in any other sequenced genome, but seven full-length and three truncated isoforms exist in the T. vaginalis genome. However, out of these, only FR1 has an affinity for flavins, i.e. FMN, FAD and riboflavin, which is high enough to be of physiological relevance. Although there are no relevant changes in the gene sequence or any alterations of the predicted FR1-mRNA structure in any of the strains studied, FR1 is not expressed in highly metronidazole-resistant strains. Transfection of a metronidazole-resistant clinical isolate (B7268), which does not express any detectable amounts of FR, with a plasmid bearing a functional FR1 gene nearly completely restored metronidazole sensitivity. Our results indicate that FR1 has a significant role in the emergence of metronidazole resistance in T. vaginalis.
authors.affiliation: Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Leitsch
authors.forename: Brian D
authors.initials: BD
authors.lastname: Janssen
authors.forename: Daniel
authors.initials: D
authors.lastname: Kolarich
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Johnson
authors.forename: Michael
authors.initials: M
authors.lastname: Duchêne
mesh_terms: D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D038181:FMN Reductase / Q000235:genetics / Q000378:metabolism*; D005415:Flavins / Q000378:metabolism*; D017125:Genes, Protozoan; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008795:Metronidazole / Q000494:pharmacology*; D020033:Protein Isoforms / Q000378:metabolism; D014246:Trichomonas vaginalis / Q000201:enzymology* / Q000235:genetics / Q000302:isolation & purification
chemical_list: D000981:Antiprotozoal Agents; D005415:Flavins; D020033:Protein Isoforms; D008795:Metronidazole; D006861:Hydrogen Peroxide; D038181:FMN Reductase