Journal of Antimicrobial Chemotherapy, Vol 41, 67-75, Copyright © 1998 by The British Society for Antimicrobial Chemotherapy
MA Jorgensen, J Manos, GL Mendz and SL Hazell
The effects of metronidazole on catalase-positive and spontaneous
catalase-negative mutants of Helicobacter pylori were studied to
investigate whether the action of metronidazole on this microaerophilic
organism occurs by reactive oxygen species generated by futile cycling or
by the reduction of metronidazole to its active form. Increased sensitivity
would be expected to occur in catalase-negative mutants if the mode of
action of metronidazole was mediated through reactive oxygen species that
may result from futile cycling of metronidazole. Two strains, RU1 and N6,
were found to mutate spontaneously to a catalase-negative phenotype. The
catalase-positive strain RU1(KatA+) and its catalase-negative counterpart
RU1(KatA-) were sensitive to metronidazole, with MICs of 0.5 mg/L. The
metronidazole-sensitive strain RU1(KatA-) lost viability at a rate similar
to the parent RU1(KatA+) strain in the presence of 10 mg/L of
metronidazole. Stable resistance to metronidazole was induced in RU1(KatA+)
and RU1(KatA-) by passaging these strains in the presence of metronidazole.
The catalase- positive and catalase-negative strains, N6(KatA+) and
N6(KatA-), were resistant to metronidazole, with MICs of 96 mg/L. These
observations indicated that the presence or absence of catalase activity
did not affect the susceptibility of strains to metronidazole. The
metabolism of metronidazole by H. pylori was investigated by 14N-NMR
spectroscopy. Metronidazole was reduced in sensitive, catalase-positive and
catalase- negative strains. Metronidazole-resistant cells reduced the 5-
nitroimidazole more slowly, suggesting that resistance is achieved through
the prevention or inhibition of metronidazole reduction.
ORIGINAL ARTICLES
The mode of action of metronidazole in Helicobacter pylori: futile cycling or reduction?
School of Microbiology and Immunology, University of New South Wales, Sydney, Australia.
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