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Drug resistance in Giardia duodenalis
Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3010, Australia..
Univ Melbourne, Inst Bio21, Parkville, Vic 3010, Australia..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
Univ Melbourne, Inst Bio21, Parkville, Vic 3010, Australia..
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2015 (English)In: Biotechnology Advances, ISSN 0734-9750, E-ISSN 1873-1899, Vol. 33, no 6, 888-901 p.Article, review/survey (Refereed) Published
Abstract [en]

Giardia duodenalis is a microaerophilic parasite of the human gastrointestinal tract and a major contributor to diarrheal and post-infectious chronic gastrointestinal disease world-wide. Treatment of G. duodenalis infection currently relies on a small number of drug classes. Nitroheterocyclics, in particular metronidazole, have represented the front line treatment for the last 40 years. Nitroheterocyclic-resistant G. duodenalis have been isolated from patients and created in vitro, prompting considerable research into the biomolecular mechanisms of resistance. These compounds are redox-active and are believed to damage proteins and DNA after being activated by oxidoreductase enzymes in metabolically active cells. In this review, we explore the molecular phenotypes of nitroheterocyclic-resistant G. duodenalis described to date in the context of the protisfs unusual glycolytic and antioxidant systems. We propose that resistance mechanisms are likely to extend well beyond currently described resistance-associated enzymes (i.e., pyruvate ferredoxin oxidoreductases and nitroreductases), to include NAD(P)H- and flavin-generating pathways, and possibly redox-sensitive epigenetic regulation. Mechanisms that allow G. duodenalis to tolerate oxidative stress may lead to resistance against both oxygen and nitroheterocyclics, with implications for clinical control. The present review highlights the potential for systems biology tools and advanced bioinformatics to further investigate the multifaceted mechanisms of nitroheterocyclic resistance in this important pathogen.

Place, publisher, year, edition, pages
2015. Vol. 33, no 6, 888-901 p.
Keyword [en]
Giardia, Nitroheterocyclic, Drug resistance, Metronidazole, Nitazoxanide, Furazolidone, NAD(P)H oxidoreductase, Sir2 NAD-dependent histone deacetylase, Treatment failure
National Category
Medical Biotechnology
Identifiers
URN: urn:nbn:se:uu:diva-267484DOI: 10.1016/j.biotechadv.2015.04.009ISI: 000362379900017PubMedID: 25922317OAI: oai:DiVA.org:uu-267484DiVA: diva2:873394
Available from: 2015-11-24 Created: 2015-11-24 Last updated: 2017-12-01Bibliographically approved

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Ma'ayeh, Showgy Y.Svärd, Staffan G.

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