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dc.contributor.authorEmery, SJ
dc.contributor.authorBaker, L
dc.contributor.authorAnsell, BRE
dc.contributor.authorMirzaei, M
dc.contributor.authorHaynes, PA
dc.contributor.authorMcConville, MJ
dc.contributor.authorSvard, SG
dc.contributor.authorJex, AR
dc.date.accessioned2020-12-17T03:25:59Z
dc.date.available2020-12-17T03:25:59Z
dc.date.issued2018-03-13
dc.identifierpii: 4931738
dc.identifier.citationEmery, S. J., Baker, L., Ansell, B. R. E., Mirzaei, M., Haynes, P. A., McConville, M. J., Svard, S. G. & Jex, A. R. (2018). Differential protein expression and post-translational modifications in metronidazole-resistant Giardia duodenalis. GIGASCIENCE, 7 (4), https://doi.org/10.1093/gigascience/giy024.
dc.identifier.issn2047-217X
dc.identifier.urihttp://hdl.handle.net/11343/254883
dc.description.abstractBackground: Metronidazole (Mtz) is the frontline drug treatment for multiple anaerobic pathogens, including the gastrointestinal protist, Giardia duodenalis. However, treatment failure is common and linked to in vivo drug resistance. In Giardia, in vitro drug-resistant lines allow controlled experimental interrogation of resistance mechanisms in isogenic cultures. However, resistance-associated changes are inconsistent between lines, phenotypic data are incomplete, and resistance is rarely genetically fixed, highlighted by reversion to sensitivity after drug selection ceases or via passage through the life cycle. Comprehensive quantitative approaches are required to resolve isolate variability, fully define Mtz resistance phenotypes, and explore the role of post-translational modifications therein. Findings: We performed quantitative proteomics to describe differentially expressed proteins in 3 seminal Mtz-resistant lines compared to their isogenic, Mtz-susceptible, parental line. We also probed changes in post-translational modifications including protein acetylation, methylation, ubiquitination, and phosphorylation via immunoblotting. We quantified more than 1,000 proteins in each genotype, recording substantial genotypic variation in differentially expressed proteins between isotypes. Our data confirm substantial changes in the antioxidant network, glycolysis, and electron transport and indicate links between protein acetylation and Mtz resistance, including cross-resistance to deacetylase inhibitor trichostatin A in Mtz-resistant lines. Finally, we performed the first controlled, longitudinal study of Mtz resistance stability, monitoring lines after cessation of drug selection, revealing isolate-dependent phenotypic plasticity. Conclusions: Our data demonstrate understanding that Mtz resistance must be broadened to post-transcriptional and post-translational responses and that Mtz resistance is polygenic, driven by isolate-dependent variation, and is correlated with changes in protein acetylation networks.
dc.languageEnglish
dc.publisherOXFORD UNIV PRESS
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleDifferential protein expression and post-translational modifications in metronidazole-resistant Giardia duodenalis
dc.typeJournal Article
dc.identifier.doi10.1093/gigascience/giy024
melbourne.affiliation.departmentBiochemistry and Molecular Biology
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentVeterinary Biosciences
melbourne.source.titleGigaScience
melbourne.source.volume7
melbourne.source.issue4
melbourne.identifier.arcLP120200122
dc.rights.licenseCC BY
melbourne.elementsid1325810
melbourne.contributor.authorJex, Aaron
melbourne.contributor.authorMcConville, Malcolm
melbourne.contributor.authorEmery, Samantha
melbourne.contributor.authorAnsell, Brendan
melbourne.contributor.authorBaker, Louise
dc.identifier.eissn2047-217X
melbourne.identifier.fundernameidAUST RESEARCH COUNCIL, LP120200122
melbourne.accessrightsOpen Access


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