Metronidazole activation is mutagenic and causes DNA fragmentation in Helicobacter pylori and in Escherichia coli containing a cloned H. pylori rdxA plus (nitroreductase) gene

Much of the normal high sensitivity of wild-type Helicobacter pylori to met ronidazole (Mtz) depends on rdxA (HP0954), a gene encoding a novel nitrored uctase that catalyzes the conversion of Mtz from a harmless prodrug to a ba ctericidal agent. Here we report that levels of Mtz that partially inhibit growth stimulate forward mutation to rifampin resistance in rdxA(+) (Mtz(s) ) and also in rdxA (Mtz(r)) 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 off. coli carrying rdxA(+) indicated that CG-to-GC transversions and AT-to-GC transitions are induced more freq uently than other base substitutions. Alkaline gel electrophoretic tests sh owed that Mtz concentrations near or higher than the MIC for growth also ca used 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. Co culture of Mtz(s) H. pylori with E. coli (highly resistant to Mtz) in the p resence of Mtz did not stimulate forward mutation in E. coli, indicating th at the mutagenic and bactericidal products of Mtz metabolism do not diffuse significantly to neighboring (bystander) cells. Our results suggest that t he widespread use of Mtz against other pathogens in people chronically infe cted 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 antimic robials.