Saghaug, C. S., Klotz, C., Kallio, J. P., Brattbakk, H.-R., Stokowy, T., Aebischer, T., … Hanevik, K. (2019). <p>Genetic variation in metronidazole metabolism and oxidative stress pathways in clinical<em> Giardia lamblia</em> assemblage A and B isolates</p>. Infection and Drug Resistance, Volume 12, 1221–1235. https://doi.org/10.2147/idr.s177997
Genetic variation in metronidazole metabolism and oxidative stress pathways in clinical Giardia lamblia assemblage A and B isolates
|Author:||Saghaug, Christina S.1,2; Klotz, Christian3; Kallio, Juha P.4;|
1Department 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, Norway
|Online Access:||PDF Full Text (PDF, 2.7 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2019102134045
Dove Medical Press,
|Publish Date:|| 2019-10-21
Purpose: 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.
Infection and drug resistance
|Pages:||1221 - 1235|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This study was supported by the University of Bergen, the Norwegian National Advisory Unit on Tropical Infectious Diseases, Department of Medicine, Haukeland University Hospital, Helse Vest and Norsk overvaakningssystem for antibiotikaresistens hos mikrober (NORM).
© 2019 Saghaug et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).