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

G. Sisson, J. Y. Jeong, A. Goodwin, L. Bryden, N. Rossler, S. Lim-Morrison, A. Raudonikiene, D. E. Berg, P. S. Hoffman

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

124 Citas (Scopus)

Resumen

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+ (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 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 Mtz(s) 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.

Idioma originalEnglish
Páginas (desde-hasta)5091-5096
Número de páginas6
PublicaciónJournal of Bacteriology
Volumen182
N.º18
DOI
EstadoPublished - 2000
Publicado de forma externa

ASJC Scopus Subject Areas

  • Microbiology
  • Molecular Biology

Huella

Profundice en los temas de investigación de 'Metronidazole activation is mutagenic and causes DNA fragmentation in Helicobacter pylori and in Escherichia coli containing a cloned H. pylori rdxA+ (nitroreductase) gene'. En conjunto forman una huella única.

Citar esto