Two amino acids mutation of ferric uptake regulator determines Helicobacter pylori resistance to metronidazole.
Metronidazole (Mtz) is a prodrug that is converted to its active form when its nitro group is reduced and superoxide radicals are generated. The superoxide radicals are directly toxic to the bacterium. On the other hand, the transcriptional regulator, ferric uptake regulator (Fur), of Helicobacter pylori is a direct suppressor of the iron-cofactored superoxide dismutase SodB, which is essential for protection against superoxide attack. Here, we demonstrate that in some Mtz-resistant strains, SodB activity is induced in a dose-dependent manner on exposure to Mtz. Further, under Mtz exposure, the generation of superoxide radicals in Mtz-resistant strains was significantly reduced as compared with that in the Mtz-susceptible strains. These Mtz-resistant strains were found to carry amino acids mutation of Fur (C78Y, P114S; mutant-type Fur). The binding affinity of the mutant-type Fur to an operator sequence on the sodB promoter (Fur-Box) was significantly reduced. Our approach demonstrated that SodB expression is derepressed by mutant-type Fur, which is associated with the development of Mtz resistance.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Hitoshi
H
Tsugawa
Hidekazu
H
Suzuki
Kazue
K
Satoh
Kenro
K
Hirata
Juntaro
J
Matsuzaki
Yoshimasa
Y
Saito
Makoto
M
Suematsu
Toshifumi
T
Hibi
D000596:Amino Acids / Q000235:genetics*; D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000737:chemistry / Q000378:metabolism; D016480:Helicobacter pylori / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D008795:Metronidazole / Q000378:metabolism / Q000494:pharmacology*; D009154:Mutation; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism
D000596:Amino Acids; D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D016166:Free Radical Scavengers; D012097:Repressor Proteins; C068477:ferric uptake regulating proteins, bacterial; D013481:Superoxides; D008795:Metronidazole; D013482:Superoxide Dismutase