ArticleThe FEBS journal2009
Characterization of the NAD(P)H oxidase and metronidazole reductase activities of the RdxA nitroreductase of Helicobacter pylori.
Article in The FEBS journal, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 61 citations in OpenAlex.
- Synthesis and In Silico Study of Pectolinarigenin-Metronidazole Hybrid Molecule as Anti-Molecules (Basel, Switzerland) · 2026Article
- Metronidazole and ether derivatives target Helicobacter pylori via simultaneous stress induction and inhibition.Nature microbiology · 2026Article
- 2-oxoglutarate:acceptor oxidoreductase-catalyzed redox cycling effectively targets coccoid forms of Helicobacter pylori.Nature communications · 2025Article
- RdxA-independent mechanism ofFrontiers in microbiology · 2025Article
- Loureirin A is a narrow-spectrum antimicrobial agent againstAntimicrobial agents and chemotherapy · 2024Article
- Functional determination of site-mutations inFrontiers in cell and developmental biology · 2024Article
- Levofloxacin+Tetracycline Quadruple Regimen for Eradication ofMiddle East journal of digestive diseases · 2023Article
- Single- and Two-Electron Reduction of Nitroaromatic Compounds by Flavoenzymes: Mechanisms and Implications for Cytotoxicity.International journal of molecular sciences · 2021Review
- FBPAII and rpoBC, the Two Novel Secreted Proteins Identified by the Proteomic Approach from a Comparative Study between Antibiotic-Sensitive and Antibiotic-Resistant Helicobacter pylori-Associated Gastritis Strains.Infection and immunity · 2021Article
- Genetically Encoded Activators of Small Molecules for Imaging and Drug Delivery.Angewandte Chemie (International ed. in English) · 2020Review
- Amixicile: A Concept Therapeutic for Treatment of Chronic Anaerobic Infections.British journal of gastroenterology · 2020Article
- Analysis of core protein clusters identifies candidate variable sites conferring metronidazole resistance inGastroenterology report · 2019Article
- Transcriptomics Indicates Active and Passive Metronidazole Resistance Mechanisms in Three SeminalFrontiers in microbiology · 2017Article
- The Helicobacter pylori CZB Cytoplasmic Chemoreceptor TlpD Forms an Autonomous Polar Chemotaxis Signaling Complex That Mediates a Tactic Response to Oxidative Stress.Journal of bacteriology · 2016Article
- Molecular and Proteomic Analysis of Levofloxacin and Metronidazole ResistantFrontiers in microbiology · 2016Article
- Comparative characterisation of two nitroreductases from Giardia lamblia as potential activators of nitro compounds.International journal for parasitology. Drugs and drug resistance · 2015Article
- Preclinical studies of amixicile, a systemic therapeutic developed for treatment of Clostridium difficile infections that also shows efficacy against Helicobacter pylori.Antimicrobial agents and chemotherapy · 2014Article
- Response to metronidazole and oxidative stress is mediated through homeostatic regulator HsrA (HP1043) in Helicobacter pylori.Journal of bacteriology · 2014Article
- Contingency nature of Helicobacter bizzozeronii oxygen-insensitive NAD(P)H-nitroreductase (HBZC1_00960) and its role in metronidazole resistance.Veterinary research · 2013Article
- Structure of RdxA--an oxygen-insensitive nitroreductase essential for metronidazole activation in Helicobacter pylori.The FEBS journal · 2012Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Metronidazole (MTZ) is widely used in combination therapies against the human gastric pathogen Helicobacter pylori. Resistance to this drug is common among clinical isolates and results from loss-of-function mutations in rdxA, which encodes an oxygen-insensitive nitroreductase. The RdxA-associated MTZ-reductase activity of H. pylori is lost upon cell disruption. Here we provide a mechanistic explanation for this phenomenon. Under aerobic conditions, His6-tagged RdxA protein (purified from Escherichia coli), catalyzed NAD(P)H-dependent reductions of nitroaromatic and quinone substrates including nitrofurazone, nitrofurantoin, furazolidone, CB1954 and 1,4-benzoquinone, but not MTZ. Unlike other nitroreductases, His6-RdxA exhibited potent NAD(P)H-oxidase activity (k(cat) = 2.8 s(-1)) which suggested two possible explanations for the role of oxygen in MTZ reduction: (a) NAD(P)H-oxidase activity promotes cellular hypoxia (nonspecific reduction of MTZ), and (b) molecular oxygen out-competes MTZ for reducing equivalents. The first hypothesis was eliminated upon finding that rdxA expression, although increasing MTZ toxicity in both E. coli and H. pylori constructs, did not increase paraquat toxicity, even though both are of similar redox potential. The second hypothesis was confirmed by demonstrating NAD(P)H-dependent MTZ-reductase activity (apparent K(m) = 122 +/- 58 microM, k(cat) = 0.24 s(-1)) under strictly anaerobic conditions. The MTZ-reductase activity of RdxA was 60 times greater than for NfsB (E. coli NTR), but 10 times lower than the NADPH-oxidase activity. Whether molecular oxygen directly competes with MTZ or alters the redox state of the FMN cofactors is discussed.
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