Metronidazole requires reductive activation within anaerobic organisms. The reason aerobic bacteria are resistant to metronidazole is best explained by:

• A Aerobic bacteria lack the nitroreductase enzyme needed to activate metronidazole
• B Aerobic bacteria express efflux pumps that export metronidazole before activation
• C In aerobic organisms, the partially reduced nitro radical anion intermediate is rapidly re-oxidised by molecular oxygen before it can damage DNA, regenerating intact metronidazole — the 'futile cycle' ✓
• D Aerobic organisms have a higher intracellular pH that prevents metronidazole from entering

Explanation

Metronidazole is a prodrug that is reduced by ferredoxin-linked electron transport proteins (nitroreductases) in strict anaerobes to reactive nitro radical anions and other reactive intermediates. These radicals cause DNA strand breaks. In aerobic organisms, molecular oxygen immediately re-oxidises the nitro radical anion back to the parent compound (futile redox cycling), preventing accumulation of the cytotoxic intermediate and explaining resistance. This is why metronidazole has a selective anaerobic and microaerophilic spectrum. Resistance in clinical Helicobacter pylori strains typically results from mutations in rdxA (encoding the oxygen-insensitive nitroreductase) rather than efflux.

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

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