Metronidazole resistance in Helicobacter pylori is mediated by which specific molecular mechanism?

• A Overexpression of NADH oxidase in H. pylori scavenges the nitro radical anion before it can damage DNA
• B Acquisition of metronidazole-inactivating methyltransferase on a conjugative transposon from Bacteroides species
• C Upregulation of drug efflux pump HP1466 reduces intracellular metronidazole concentrations
• D Loss-of-function mutations in rdxA (encoding oxygen-insensitive nitroreductase) and frxA prevent reductive activation of metronidazole to its toxic nitro radical anion ✓

Explanation

Metronidazole requires reductive activation within the anaerobic or microaerophilic microbial cell. The nitro group of metronidazole is reduced by the nitroreductase system (primarily encoded by rdxA in H. pylori and pyruvate:ferredoxin oxidoreductase in anaerobes) to generate a highly reactive nitro radical anion that causes oxidative DNA strand breaks. In H. pylori, loss-of-function mutations in rdxA (encoding an oxygen-insensitive nitroreductase) are the primary mechanism of metronidazole resistance — the drug is not activated and therefore cannot damage DNA. Secondary mutations in frxA (another flavin oxidoreductase) compound this resistance. This resistance pattern is clinically significant: H. pylori metronidazole resistance rates in India exceed 60–70%, which is why regimens increasingly use clarithromycin-based or bismuth-containing quadruple therapy or vonoprazan-based regimens.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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