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

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Abstract
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 inrdxA+ (Mtzs) and also inrdxA (Mtzr) H. pylori strains, and that expression of rdxA in Escherichia coliresults in equivalent Mtz-induced mutation. A reversion test using defined lac tester strains of E. coli carryingrdxA+ 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 carryingrdxA+, suggesting that this damage may account for most of the bactericidal action of Mtz. Coculture of MtzsH. 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 withH. pylori may stimulate mutation and recombination inH. pylori, thereby speeding host-specific adaptation, the evolution of virulence, and the emergence of resistance against Mtz and other clinically useful antimicrobials.