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Sökning: id:"swepub:oai:DiVA.org:uu-356813" > Differential protei...

Differential protein expression and post-translational modifications in metronidazole-resistant Giardia duodenalis

Emery, Samantha J. (författare)
Walter & Eliza Hall Inst Med Res, Populat Hlth & Immun Div, Melbourne, Vic, Australia
Baker, Louise (författare)
Walter & Eliza Hall Inst Med Res, Populat Hlth & Immun Div, Melbourne, Vic, Australia;Univ Melbourne, Fac Vet & Agr Sci, Melbourne, Vic, Australia
Ansell, Brendan R. E. (författare)
Walter & Eliza Hall Inst Med Res, Populat Hlth & Immun Div, Melbourne, Vic, Australia;Univ Melbourne, Fac Vet & Agr Sci, Melbourne, Vic, Australia
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Mirzaei, Mehdi (författare)
Macquarie Univ, Fac Sci, Chem & Biomol Sci, N Ryde, NSW, Australia;Macquarie Univ, Australian Proteome Anal Facil, N Ryde, NSW, Australia
Haynes, Paul A. (författare)
Macquarie Univ, Fac Sci, Chem & Biomol Sci, N Ryde, NSW, Australia
McConville, Malcom J. (författare)
Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Melbourne, Vic, Australia
Svärd, Staffan (författare)
Uppsala universitet,Mikrobiologi
Jex, Aaron R. (författare)
Walter & Eliza Hall Inst Med Res, Populat Hlth & Immun Div, Melbourne, Vic, Australia;Univ Melbourne, Fac Vet & Agr Sci, Melbourne, Vic, Australia
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 (creator_code:org_t)
2018-03-13
2018
Engelska.
Ingår i: GigaScience. - : OXFORD UNIV PRESS. - 2047-217X. ; 7:4
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • Background: 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Microbiology in the medical area (hsv//eng)

Nyckelord

Giardia duodenalis
quantitative proteomics
metronidazole
drug resistance
protein post-translational modifications

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