Oxidases and reductases are involved in metronidazole sensitivity in Helicobacter pylori

Trend, Mark A.; Jorgensen, Margaret; Hazell, Stuart L.; Mendz, George L.

doi:10.1016/s1357-2725(00)00085-6

Cited by 24 publications

(24 citation statements)

References 31 publications

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“…This result is in agreement with Marais et al 33 who suggested that an MTZ resistance phenotype may arise in H. pylori without mutation in rdxA or frxA. Interestingly, several groups 22,[34][35][36][37] and genome sequence annotation [38][39][40] suggest other putative redox systems that may play a role in MTZ resistance. These include fdxB (encoding a ferredoxin-like protein), fdxA (ferredoxin), fldA (flavodoxin), oorD (the g-subunit of 2-oxoglutarate oxidoreductase and porD (the g-subunit of pyruvate ferredoxin oxidoreductase).…”

Section: R5 G C T a C -A A A A A T T C T A A A A A A A T A A A G G A supporting

confidence: 88%

Genetic analysis of Helicobacter pylori clinical isolates suggests resistance to metronidazole can occur without the loss of functional rdxA

Kim¹,

Joo²,

Lee³

et al. 2009

J Antibiot

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Resistance to metronidazole (MTZ) in Helicobacter pylori is associated with mutations in rdxA, encoding an oxygen-insensitive NADPH nitroreductase, and mutations in frxA, encoding a NAD(P)H-flavin oxidoreductase. Despite this association, the strict correlation of MTZ resistance with mutations in rdxA or frxA is still controversial. In this study, rdxA allelic replacement was used to distinguish resistance-associated nucleotide mutations from the natural genetic diversity of H. pylori. Replacement with truncated rdxA resulted in MTZ resistance, whereas replacement with missense-mutated rdxA from resistant clinical isolates failed to yield MTZ resistance. Thus, although truncation of rdxA confers MTZ resistance in G27 H. pylori, MTZ resistance found in other clinical isolates is not due to the identified amino-acid substitutions. Three of our MTZ-resistant clinical isolates expressed functional rdxA and two of these also encoded full-length frxA. Therefore, MTZ resistance can arise in H. pylori possessing functional rdxA, suggesting that other factors are involved in MTZ resistance.

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Section: R5 G C T a C -A A A A A T T C T A A A A A A A T A A A G G A supporting

confidence: 88%

Genetic analysis of Helicobacter pylori clinical isolates suggests resistance to metronidazole can occur without the loss of functional rdxA

Kim¹,

Joo²,

Lee³

et al. 2009

J Antibiot

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“…Early studies showed that the oxygen tension has a large impact on the resistance of H. pylori to Mtr (23,(31)(32)(33), and several investigations have linked the activities of specific oxidoreductases to the Mtr-susceptible phenotype of the bacterium (9,23,36). Three disulfide reduction activities, which use dithiobis-2-nitrobenzoic acid (DTNB), oxidized glutathione (GSSG) and NADH, or ferredoxin (Fdx) and NADH as substrates, were identified in H. pylori (12).…”

mentioning

confidence: 99%

A Redox Basis for Metronidazole Resistance in Helicobacter pylori

Kaakoush

Asencio

Mégraud

et al. 2009

Antimicrob Agents Chemother

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Metronidazole resistance in Helicobacter pylori has been attributed to mutations in rdxA or frxA. Insufficient data correlating RdxA and/or FrxA with the resistant phenotype, and the emergence of resistant strains with no mutations in either rdxA or frxA, indicated that the molecular basis of H. pylori resistance to metronidazole required further characterization. The rdxA and frxA genes of four matched pairs of metronidazole-susceptible and -resistant strains were sequenced. The resistant strains had mutations in either rdxA, frxA, neither gene, or both genes. The reduction rates of five substrates suggested that metabolic differences between susceptible and resistant strains cannot be explained only by mutations in rdxA and/or frxA. A more global approach to understanding the resistance phenotype was taken by employing two-dimensional gel electrophoresis combined with tandem mass spectrometry analyses to identify proteins differentially expressed by the matched pair of strains with no mutations in rdxA or frxA. Proteins involved in the oxireduction of ferredoxin were downregulated in the resistant strain. Other redox enzymes, such as thioredoxin reductase, alkyl hydroperoxide reductase, and superoxide dismutase, showed a pI change in the resistant strain. The data suggested that metronidazole resistance involved more complex metabolic changes than specific gene mutations, and they provided evidence of a role for the intracellular redox potential in the development of resistance.Metronidazole (Mtr) is an important component of therapeutic regimens that currently are used to treat many microbial infections. Metronidazole is considered a prodrug whose uptake and activation requires intracellular reduction, resulting in the production of cytotoxic short-lived radicals and other reactive species (29). 5-Nitroimidazole is activated via interactions with redox systems capable of reducing the low-potential (Ϫ415 mV) nitro group in position 5 of the imidazole ring (29). This property makes metronidazole effective against organisms in a low-intracellular-redox state, such as anaerobic bacteria and protozoa, as well as some microaerophiles, such as Campylobacter spp. and Helicobacter pylori (16).Helicobacter pylori is found in the gastric mucous layer or adhering to the epithelial lining of the human stomach and is one of the most prevalent infections in humans (1,19,39). The frequent use of metronidazole has resulted in increased resistance to the antibiotic by H. pylori. The emergence of resistant isolates that do not respond to the drug fostered an interest in understanding the primary causes of resistance to metronidazole in this bacterium. Extensive investigations of H. pylori established that the main causes of metronidazole resistance are mutations in the gene rdxA or frxA (6,7,14,15). However, insufficient data correlating the oxygen-insensitive nitroreductase RdxA and/or the NAD(P)H flavin oxidoreductase FrxA with the resistant phenotype and the fact that a small percentage of resistant strains do not have mutat...

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“…bacteria in media containing increasing amounts of Mtr. 3 Minimum inhibitory concentrations (MIC) of Mtr were determined by using an E-test strip. In situ reduction of Mtr was investigated by employing 14 N-NMR spectroscopy to follow the time-evolution of the nitro moiety of the imidazole ring as described previously.…”

Section: Methodsmentioning

confidence: 99%

“…In situ reduction of Mtr was investigated by employing 14 N-NMR spectroscopy to follow the time-evolution of the nitro moiety of the imidazole ring as described previously. 3 Glutathione reduction was measured in suspensions of bacterial lysates by employing 1 H-NMR spectroscopy. 5 …”

Section: Methodsmentioning

confidence: 99%

Oxidases and reductases are involved in metronidazole sensitivity in Helicobacter pylori

Cited by 24 publications

References 31 publications

Genetic analysis of Helicobacter pylori clinical isolates suggests resistance to metronidazole can occur without the loss of functional rdxA

Genetic analysis of Helicobacter pylori clinical isolates suggests resistance to metronidazole can occur without the loss of functional rdxA

A Redox Basis for Metronidazole Resistance in Helicobacter pylori

Intracellular redox status and antibiotic resistance in enterogastric micro-aerophilic bacteria: evidence for the ‘scavenging of oxygen’ hypothesis

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