Mouse-Colonizing Helicobacter pylori SS1 Is Unusually Susceptible to Metronidazole Due to Two Complementary Reductase Activities

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Abstract
In most strains of Helicobacter pylori , mutational inactivation of the rdxA (HP0954) gene, which encodes a nitroreductase that converts metronidazole (MTZ) from a harmless prodrug to a mutagenic and bacteriocidal product, is sufficient to make this pathogen resistant to clinically significant levels of MTZ. Here we report that SS1, a strain with the special ability to colonize mice, is unusual in being susceptible to very low concentrations of MTZ (0.5 μg/ml) and in being especially difficult to mutate to MTZ resistance (Mtz r ). These phenotypic traits were traced to expression in this strain of the normally quiescent H. pylori frxA gene (HP0642, an rdxA paralog) along with rdxA. Transformation tests using rdxA :: cam and frxA :: kan insertion mutant DNAs, with selection solely for the chloramphenicol and kanamycin resistance markers, and sequence analyses of frxA in spontaneous Mtz r derivatives of rdxA null mutant strains each showed that the development of Mtz r in SS1 required inactivation of both rdxA and frxA . Inactivation of either gene alone left SS1 susceptible to MTZ, although it was readily mutable from an MTZ-susceptible to an Mtz r phenotype. Reverse transcriptase PCR tests showed that frxA mRNA was at least 10-fold more abundant in SS1 than in reference strain 26695. It is proposed that these reductases play primarily nutritional roles during bacterial growth.