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dc.contributor.authorSaghaug, Christina Skåren_US
dc.contributor.authorKlotz, Christianen_US
dc.contributor.authorKallio, Juha Pekkaen_US
dc.contributor.authorBrattbakk, Hans-Richarden_US
dc.contributor.authorStokowy, Tomaszen_US
dc.contributor.authorAebischer, Tonien_US
dc.contributor.authorKursula, Inarien_US
dc.contributor.authorLangeland, Ninaen_US
dc.contributor.authorHanevik, Kurten_US
dc.date.accessioned2020-08-07T07:26:46Z
dc.date.available2020-08-07T07:26:46Z
dc.date.issued2019-05-10
dc.PublishedSaghaug CS, Klotz C, Kallio J, Brattbakk H, Stokowy T, Aebischer T, Kursula I, Langeland N, Hanevik K. Genetic variation in metronidazole metabolism and oxidative stress pathways in clinical giardia lamblia assemblage A and B isolates. Infection and Drug Resistance. 2019;12:1221-1235eng
dc.identifier.issn1178-6973
dc.identifier.urihttps://hdl.handle.net/1956/23540
dc.description.abstractPurpose: Treatment-refractory Giardia cases have increased rapidly within the last decade. No markers of resistance nor a standardized susceptibility test have been established yet, but several enzymes and their pathways have been associated with metronidazole (MTZ) resistant Giardia. Very limited data are available regarding genetic variation in these pathways. We aimed to investigate genetic variation in metabolic pathway genes proposed to be involved in MTZ resistance in recently acquired, cultured clinical isolates. Methods: Whole genome sequencing of 12 assemblage A2 and 8 assemblage B isolates was done, to decipher genomic variation in Giardia. Twenty-nine genes were identified in a literature search and investigated for their single nucleotide variants (SNVs) in the coding/non-coding regions of the genes, either as amino acid changing (non-synonymous SNVs) or non-changing SNVs (synonymous). Results: In Giardia assemblage B, several genes involved in MTZ activation or oxidative stress management were found to have higher numbers of non-synonymous SNVs (thioredoxin peroxidase, nitroreductase 1, ferredoxin 2, NADH oxidase, nitroreductase 2, alcohol dehydrogenase, ferredoxin 4 and ferredoxin 1) than the average variation. For Giardia assemblage A2, the highest genetic variability was found in the ferredoxin 2, ferredoxin 6 and in nicotinamide adenine dinucleotide phosphate (NADPH) oxidoreductase putative genes. SNVs found in the ferredoxins and nitroreductases were analyzed further by alignment and homology modeling. SNVs close to the iron-sulfur cluster binding sites in nitroreductase-1 and 2 and ferredoxin 2 and 4 could potentially affect protein function. Flavohemoprotein seems to be a variable-copy gene, due to higher, but variable coverage compared to other genes investigated. Conclusion: In clinical Giardia isolates, genetic variability is common in important genes in the MTZ metabolizing pathway and in the management of oxidative and nitrosative stress and includes high numbers of non-synonymous SNVs. Some of the identified amino acid changes could potentially affect the respective proteins important in the MTZ metabolism.en_US
dc.language.isoengeng
dc.publisherDove Medical Presseng
dc.rightsAttribution-Non Commercial CC BY-NCeng
dc.rights.urihttp://creativecommons.org/licenses/by-nc/3.0/eng
dc.titleGenetic variation in metronidazole metabolism and oxidative stress pathways in clinical giardia lamblia assemblage A and B isolatesen_US
dc.typePeer reviewed
dc.typeJournal article
dc.date.updated2020-01-14T13:00:07Z
dc.description.versionpublishedVersionen_US
dc.rights.holderCopyright 2019 The Authors
dc.identifier.doihttps://doi.org/10.2147/idr.s177997
dc.identifier.cristin1714831
dc.source.journalInfection and Drug Resistance


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