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Antimicrobial Agents and Chemotherapy, February 2009, p. 458-464, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00909-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Giardia, Entamoeba, and Trichomonas Enzymes Activate Metronidazole (Nitroreductases) and Inactivate Metronidazole (Nitroimidazole Reductases) {triangledown} ,{dagger}

Dibyarupa Pal,1 Sulagna Banerjee,2 Jike Cui,2 Aaron Schwartz,2 Sudip K. Ghosh,1* and John Samuelson2

Department of Biotechnology, Indian Institute of Technology, Kharagpur, West Bengal 721302, India,1 Department of Molecular and Cell Biology, Boston University Goldman School of Dental Medicine, Boston, Massachusetts 021182

Received 8 July 2008/ Returned for modification 2 September 2008/ Accepted 7 November 2008

Infections with Giardia lamblia, Entamoeba histolytica, and Trichomonas vaginalis, which cause diarrhea, dysentery, and vaginitis, respectively, are each treated with metronidazole. Here we show that Giardia, Entamoeba, and Trichomonas have oxygen-insensitive nitroreductase (ntr) genes which are homologous to those genes that have nonsense mutations in metronidazole-resistant Helicobacter pylori isolates. Entamoeba and Trichomonas also have nim genes which are homologous to those genes expressed in metronidazole-resistant Bacteroides fragilis isolates. Recombinant Giardia, Entamoeba, and Trichomonas nitroreductases used NADH rather than the NADPH used by Helicobacter, and two recombinant Entamoeba nitroreductases increased the metronidazole sensitivity of transformed Escherichia coli strains. Conversely, the recombinant nitroimidazole reductases (NIMs) of Entamoeba and Trichmonas conferred very strong metronidazole resistance to transformed bacteria. The Ehntr1 gene of the genome project HM-1:IMSS strain of Entamoeba histolytica had a nonsense mutation, and the same nonsense mutation was present in 3 of 22 clinical isolates of Entamoeba. While ntr and nim mRNAs were variably expressed by cultured Entamoeba and Trichomonas isolates, there was no relationship to metronidazole sensitivity. We conclude that microaerophilic protists have bacterium-like enzymes capable of activating metronidazole (nitroreductases) and inactivating metronidazole (NIMs). While Entamoeba and Trichomonas displayed some of the changes (nonsense mutations and gene overexpression) associated with metronidazole resistance in bacteria, these changes did not confer metronidazole resistance to the microaerophilic protists examined here.

* Corresponding author. Mailing address: Department of Biotechnology, Indian Institute of Technology, Kharagpur, West Bengal 721302, India. Phone: 91-3222-283768. Fax: 91-3222-278707. E-mail: sudip{at}hijli.iitkgp.ernet.in

{triangledown} Published ahead of print on 17 November 2008.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, February 2009, p. 458-464, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00909-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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