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Journal of Bacteriology, September 2001, p. 5155-5162, Vol. 183, No. 17
0021-9193/01/$04.00+0   DOI: 10.1128/JB.183.17.5155-5162.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Roles of FrxA and RdxA Nitroreductases of Helicobacter pylori in Susceptibility and Resistance to Metronidazole

Jin-Yong Jeong,1 Asish K. Mukhopadhyay,1 Junko K. Akada,1 Daiva Dailidiene,1 Paul S. Hoffman,2 and Douglas E. Berg1,*

Departments of Molecular Microbiology and of Genetics, Washington University School of Medicine, St. Louis, Missouri,1 and Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada2

Received 21 December 2000/Accepted 6 June 2001

The relative importance of the frxA and rdxA nitroreductase genes of Helicobacter pylori in metronidazole (MTZ) susceptibility and resistance has been controversial. Jeong et al. (J. Bacteriol. 182:5082-5090, 2000) had interpreted that Mtzs H. pylori were of two types: type I, requiring only inactivation of rdxA to became resistant, and type II, requiring inactivation of both rdxA and frxA to become resistant; frxA inactivation by itself was not sufficient to confer resistance. In contrast, Kwon et al. (Antimicrob. Agents Chemother. 44:2133-2142, 2000) had interpreted that resistance resulted from inactivation either of frxA or rdxA. These two interpretations were tested here. Resistance was defined as efficient colony formation by single cells from diluted cultures rather than as growth responses of more dense inocula on MTZ-containing medium. Tests of three of Kwon's Mtzs strains showed that each was type II, requiring inactivation of both rdxA and frxA to become resistant. In additional tests, derivatives of frxA mutant strains recovered from MTZ-containing medium were found to contain new mutations in rdxA, and frxA inactivation slowed MTZ-induced killing of Mtzs strains. Northern blot analyses indicated that frxA mRNA, and perhaps also rdxA mRNA, were more abundant in type II than in type I strains. We conclude that development of MTZ resistance in H. pylori requires inactivation of rdxA alone or of both rdxA and frxA, depending on bacterial genotype, but rarely, if ever, inactivation of frxA alone, and that H. pylori strains differ in regulation of nitroreductase gene expression. We suggest that such regulatory differences may be significant functionally during human infection.

* Corresponding author. Mailing address: Department of Molecular Microbiology, Campus Box 8230, Washington University School of Medicine, St. Louis, MO 63110. Phone: (314) 362-2772. Fax: (314) 362-1232. E-mail: berg{at}borcim.wustl.edu.

Journal of Bacteriology, September 2001, p. 5155-5162, Vol. 183, No. 17
0021-9193/01/$04.00+0   DOI: 10.1128/JB.183.17.5155-5162.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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