Metronidazole resistance in Helicobacter pylori is mediated by which molecular mechanism?
- A Efflux pump overexpression exporting metronidazole before reduction can occur
- B Acquisition of plasmid-encoded metronidazole methyltransferase
- C Loss-of-function mutations in rdxA gene (nitroreductase encoding gene) preventing metronidazole bioactivation to cytotoxic nitroradical intermediates ✓
- D Overexpression of DNA repair enzymes counteracting DNA strand breaks
Correct answer: C. Loss-of-function mutations in rdxA gene (nitroreductase encoding gene) preventing metronidazole bioactivation to cytotoxic nitroradical intermediates
Explanation
Metronidazole is a prodrug requiring anaerobic/microaerophilic bioactivation: its 5-nitro group is reduced by bacterial nitroreductases (primarily encoded by rdxA and frxA genes in H. pylori) to cytotoxic radical intermediates that cause DNA strand breaks. Mutations or deletion in rdxA (and secondarily frxA) prevent this reduction, so no toxic metabolites are generated and the drug has no antibacterial effect. rdxA mutations are the primary resistance mechanism in H. pylori globally. Efflux pumps play a minor secondary role in some strains.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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