Metabolism of nitro drugs metronidazole and nitazoxanide in Giardia lamblia: characterization of a novel nitroreductase (GlNR2).

Müller, Joachim; Schildknecht, Patricia; Müller, Norbert (2013). Metabolism of nitro drugs metronidazole and nitazoxanide in Giardia lamblia: characterization of a novel nitroreductase (GlNR2). Journal of antimicrobial chemotherapy, 68(8), pp. 1781-1789. Oxford University Press 10.1093/jac/dkt106

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OBJECTIVES The protozoan parasite Giardia lamblia causes giardiasis, a persistent diarrhoea. Nitro drugs such as the nitroimidazole metronidazole and the nitrothiazolide nitazoxanide are used for the treatment of giardiasis. Nitroreductases may play a role in activating these drugs. G. lamblia contains two nitroreductases, GlNR1 and GlNR2. The aim of this work was to elucidate the role of GlNR2. METHODS Expression of GlNR2 was analysed by reverse transcription PCR. Recombinant GlNR2 was overexpressed in G. lamblia and drug susceptibility was analysed. Recombinant GlNR2 was subjected to functional assays. Escherichia coli expressing full-length or truncated GlNR1 and GlNR2 were grown in the presence of nitro compounds. Using E. coli reporter strains for nitric oxide and DNA damage responses, we analysed whether GlNR1 and GlNR2 elicited the respective responses in the presence, or absence, of the drugs. RESULTS G. lamblia trophozoites overexpressing GlNR2 were less susceptible to both nitro drugs as compared with control trophozoites. GlNR2 was a functional nitroreductase when expressed in E. coli. E. coli expressing GlNR1 was more susceptible to metronidazole under aerobic and semi-aerobic and to nitazoxanide under semi-aerobic growth conditions. E. coli expressing GlNR2 was not susceptible to either drug. In reporter strains, GlNR1, but not GlNR2, elicited nitric oxide and DNA repair responses, even in the absence of nitro drugs. CONCLUSIONS These findings suggest that GlNR2 is an active nitroreductase with a mode of action different from that of GlNR1. Thus, susceptibility to nitro drugs may depend not only on activation, but also on inactivation of the drugs by specific nitroreductases.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Müller, Joachim and Müller, Norbert

Subjects:

600 Technology > 630 Agriculture

ISSN:

0305-7453

Publisher:

Oxford University Press

Language:

English

Submitter:

Susanne Portner

Date Deposited:

06 Aug 2014 16:52

Last Modified:

27 Apr 2018 09:11

Publisher DOI:

10.1093/jac/dkt106

PubMed ID:

23580565

Uncontrolled Keywords:

drug susceptibility, drug targets, mode of action

BORIS DOI:

10.7892/boris.44747

URI:

https://boris.unibe.ch/id/eprint/44747

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