Genetic variation in metronidazole metabolism and oxidative stress pathways in clinical Giardia lamblia assemblage A and B isolates

• Main Authors: Saghaug CS, Klotz C, Kallio JP, Brattbakk HR, Stokowy T, Aebischer T, Kursula I, Langeland N, Hanevik K
• Format: Article in Journal/Newspaper
• Language: English
• Published: Dove Medical Press 2019
• Subjects: Drug metabolism; resistance; genetic analysis; metronidazole genes; ferredoxin; genetic diversity; Infectious and parasitic diseases; RC109-216; Bergen; Inari; Kallio; Norway; Saghaug
• Online Access: https://doaj.org/article/18b09c7bd7d3466b86d1572bd8dfa966

Christina S Saghaug,1,2 Christian Klotz,3 Juha P Kallio,4 Hans-Richard Brattbakk,1,5 Tomasz Stokowy,1,5 Toni Aebischer,3 Inari Kursula,4,6 Nina Langeland,1–2,7 Kurt Hanevik1,21Department of Clinical Science, University of Bergen, Bergen, Hordaland, Norway; 2Norwegian National Advisory Unit on Tropical Infectious Diseases, Department of Medicine, Haukeland University Hospital, Bergen, Hordaland, Norway; 3Department of Infectious Diseases, Unit 16 Mycotic and Parasitic Agents and Mycobacteria, Robert Koch-Institute, Berlin, Germany; 4Department of Biomedicine, University of Bergen, Bergen, Hordaland, Norway; 5Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Hordaland, Norway; 6Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; 7Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Hordaland, NorwayPurpose: 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 ...