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Antimicrobial Agents and Chemotherapy, June 2007, p. 1979-1986, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01548-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Novel Giardia lamblia Nitroreductase, GlNR1, Interacts with Nitazoxanide and Other Thiazolides{triangledown}

Joachim Müller,1* Jonathan Wastling,2 Sanya Sanderson,2 Norbert Müller,1 and Andrew Hemphill1*

Institute of Parasitology, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland,1 Departments of Pre-Clinical Science and Veterinary Pathology, Faculty of Veterinary Science, University of Liverpool, Liverpool L69 7ZJ, United Kingdom2

Received 12 December 2006/ Returned for modification 28 January 2007/ Accepted 3 April 2007

The nitrothiazole analogue nitazoxanide [NTZ; 2-acetolyloxy-N-(5-nitro-2-thiazolyl)benzamide] represents the parent compound of a class of drugs referred to as thiazolides and exhibits a broad spectrum of activities against a wide variety of helminths, protozoa, and enteric bacteria infecting animals and humans. NTZ and other thiazolides are active against a wide range of other intracellular and extracellular protozoan parasites in vitro and in vivo, but their mode of action and respective subcellular target(s) have only recently been investigated. In order to identify potential targets of NTZ and other thiazolides in Giardia lamblia trophozoites, we have developed an affinity chromatography system using the deacetylated derivative of NTZ, tizoxanide (TIZ), as a ligand. Affinity chromatography on TIZ-agarose using cell extracts of G. lamblia trophozoites resulted in the isolation of an approximately 35-kDa polypeptide, which was identified by mass spectrometry as a nitroreductase (NR) homologue (EAA43030.1). NR was overexpressed as a six-histidine-tagged recombinant protein in Escherichia coli, purified, and then characterized using an assay for oxygen-insensitive NRs with dinitrotoluene as a substrate. This demonstrated that the NR was functionally active, and the protein was designated GlNR1. In this assay system, NR activity was severely inhibited by NTZ and other thiazolides, demonstrating that the antigiardial activity of these drugs could be, at least partially, mediated through inhibition of GlNR1.

* Corresponding author. Mailing address: Institute of Parasitology, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland. Phone: 41 31 6312384. Fax: 41 31 6312477. E-mail for Joachim Müller: joachim.mueller{at}ipa.unibe.ch. E-mail for Andrew Hemphill: andrew.hemphill{at}ipa.unibe.ch

{triangledown} Published ahead of print on 16 April 2007.

Antimicrobial Agents and Chemotherapy, June 2007, p. 1979-1986, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01548-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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  • Pal, D., Banerjee, S., Cui, J., Schwartz, A., Ghosh, S. K., Samuelson, J. (2009). Giardia, Entamoeba, and Trichomonas Enzymes Activate Metronidazole (Nitroreductases) and Inactivate Metronidazole (Nitroimidazole Reductases). Antimicrob. Agents Chemother. 53: 458-464 [Abstract] [Full Text]  
  • Muller, J., Ley, S., Felger, I., Hemphill, A., Muller, N. (2008). Identification of differentially expressed genes in a Giardia lamblia WB C6 clone resistant to nitazoxanide and metronidazole. J Antimicrob Chemother 62: 72-82 [Abstract] [Full Text]  


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