Metronidazole is selectively toxic to anaerobic and microaerophilic organisms. What is the activation mechanism that makes it specific to these organisms?

• A Aerobic organisms metabolize metronidazole to an inactive sulfoxide form before it can enter the cell
• B Metronidazole is selectively transported across membranes only in bacteria with reduced pH environments
• C It acts as a prodrug activated by host liver CYP450 producing a metabolite toxic specifically to anaerobes
• D Reduction of the nitro group by ferredoxin/nitroreductase systems in anaerobes generates a cytotoxic nitroso radical intermediate that alkylates bacterial DNA ✓

Explanation

Metronidazole is a prodrug activated by reduction of its 5-nitro group within anaerobic organisms. Bacterial and protozoal electron transport proteins (ferredoxin, flavodoxin) with sufficiently negative redox potential donate electrons to metronidazole's nitro group, generating short-lived cytotoxic intermediate radicals (nitroso/hydroxylamine) that cause DNA strand breakage and inhibit DNA repair, leading to cell death. In aerobic cells the drug cannot be reduced because the redox environment is too oxidizing; oxygen would rapidly re-oxidize any reduced intermediates.

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

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