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Journal of Bacteriology, September 2000, p. 5091-5096, Vol. 182, No. 18
0021-9193/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Metronidazole Activation Is Mutagenic and Causes DNA Fragmentation in Helicobacter pylori and in Escherichia coli Containing a Cloned H. pylori rdxA+ (Nitroreductase) Gene

Gary Sisson,1 Jin-Yong Jeong,2 Avery Goodwin,1 Louis Bryden,1 Norma Rossler,1 Sabrina Lim-Morrison,1 Ausra Raudonikiene,1 Douglas E. Berg,2 and Paul S. Hoffman1,3,*

Department of Microbiology and Immunology1 and Division of Infectious Diseases, Department of Medicine,3 Dalhousie University, Halifax, Nova Scotia, Canada, and Department of Molecular Microbiology and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri2

Received 23 March 2000/Accepted 28 June 2000

Much of the normal high sensitivity of wild-type Helicobacter pylori to metronidazole (Mtz) depends on rdxA (HP0954), a gene encoding a novel nitroreductase that catalyzes the conversion of Mtz from a harmless prodrug to a bactericidal agent. Here we report that levels of Mtz that partially inhibit growth stimulate forward mutation to rifampin resistance in rdxA+ (Mtzs) and also in rdxA (Mtzr) H. pylori strains, and that expression of rdxA in Escherichia coli results in equivalent Mtz-induced mutation. A reversion test using defined lac tester strains of E. coli carrying rdxA+ indicated that CG-to-GC transversions and AT-to-GC transitions are induced more frequently than other base substitutions. Alkaline gel electrophoretic tests showed that Mtz concentrations near or higher than the MIC for growth also caused DNA breakage in H. pylori and in E. coli carrying rdxA+, suggesting that this damage may account for most of the bactericidal action of Mtz. Coculture of Mtzs H. pylori with E. coli (highly resistant to Mtz) in the presence of Mtz did not stimulate forward mutation in E. coli, indicating that the mutagenic and bactericidal products of Mtz metabolism do not diffuse significantly to neighboring (bystander) cells. Our results suggest that the widespread use of Mtz against other pathogens in people chronically infected with H. pylori may stimulate mutation and recombination in H. pylori, thereby speeding host-specific adaptation, the evolution of virulence, and the emergence of resistance against Mtz and other clinically useful antimicrobials.

* Corresponding author. Present address: Anti Infectives Research Division, SmithKline Beecham Pharmaceuticals, 1250 Collegeville Road, Collegeville, PA 19426. Phone: (610) 917-6010. Fax: (610) 917-7901. E-mail: Paul_2_Hoffman{at}sbphrd.com or phoffman{at}tupdean2.med.dal.ca.

Journal of Bacteriology, September 2000, p. 5091-5096, Vol. 182, No. 18
0021-9193/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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