Characterization of a Giardia lamblia WB C6 clone resistant to the isoflavone formononetin

Sterk, Maaike; Müller, Joachim; Hemphill, Andrew; Müller, Norbert (2007). Characterization of a Giardia lamblia WB C6 clone resistant to the isoflavone formononetin. Microbiology, 153(Pt 12), pp. 4150-8. Reading, UK: Society for General Microbiology 10.1099/mic.0.2007/010041-0

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Giardia lamblia is a common intestinal-dwelling protozoan and causes diarrhoea in humans and animals worldwide. For several years, a small number of drugs such as the 5-nitroimidazole metronidazole (MET) or the thiazolide nitazoxanide (NTZ) have been used for chemotherapy against giardiasis. However, various pre-clinical and clinical investigations revealed that antigiardial chemotherapy may be complicated by emergence of giardial resistance to these drugs. The present study addressed the question if isoflavones with antigiardial activity, such as daidzein (DAI) or formononetin (FOR), may serve as alternative compounds for treatment of giardiasis. For this purpose, the potential of G. lamblia clone WB C6 to form resistance to FOR and related isoflavones was tested in vitro. In the line of these experiments, a clone (C3) resistant to isoflavones, but sensitive to MET and NTZ, was generated. Affinity chromatography on DAI-agarose using cell-free extracts of G. lamblia trophozoites resulted in the isolation of a polypeptide of approximately 40 kDa, which was identified by mass spectrometry as a nucleoside hydrolase (NH) homologue (EAA37551.1). In a nucleoside hydrolase assay, recombinant NH hydrolysed all nucleosides with a preference for purine nucleosides and was inhibited by isoflavones. Using quantitative RT-PCR, the expression of genes that are potentially involved in resistance formation was analysed, namely NH and genes encoding variant surface proteins (VSPs, TSA417). The transcript level of the potential target NH was found to be significantly reduced in C3. Moreover, drastic changes were observed in VSP gene expression. This may indicate that resistance formation in Giardia against isoflavones is linked to, and possibly mediated by, altered gene expression. Taken together, our results suggest FOR or related isoflavones as an alternative antigiardial agent to overcome potential problems of resistance to drugs like MET or NTZ. However, the capacity of Giardia to develop resistance to isoflavones can potentially interfere with this alternative treatment of the disease.

Item Type:	Journal Article (Original Article)
Division/Institute:	05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
UniBE Contributor:	Müller, Heinz Joachim, Hemphill, Andrew, Müller, Norbert
ISSN:	1350-0872
Publisher:	Society for General Microbiology
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:53
Last Modified:	05 Dec 2022 14:16
Publisher DOI:	10.1099/mic.0.2007/010041-0
PubMed ID:	18048928
Web of Science ID:	000251931600022
URI:	https://boris.unibe.ch/id/eprint/22727 (FactScience: 36354)