A patient with Clostridium difficile colitis is treated with metronidazole. The mechanism by which metronidazole is selectively toxic to anaerobes and not to aerobic human cells is:

• A Anaerobes lack catalase and cannot detoxify the reactive metabolites of metronidazole
• B The nitro group of metronidazole is reduced to a toxic radical only in low-redox-potential environments found in anaerobic organisms, which then alkylates DNA ✓
• C Anaerobic bacteria lack the antiporter that removes metronidazole from the cell
• D Metronidazole selectively binds to anaerobic cell wall components absent in human cells

Explanation

Metronidazole is a prodrug. Its nitro group undergoes one-electron reduction to form a short-lived nitro radical anion, which is highly toxic and causes DNA strand breaks and disruption of DNA synthesis. This reduction only occurs in organisms with very low intracellular redox potential (Eh) — i.e., strict anaerobes and certain parasites (Giardia, Trichomonas, Entamoeba). In aerobic cells, oxygen rapidly reoxidizes the intermediate back to the parent compound before it can cause damage, preventing cytotoxicity. This mechanism accounts for metronidazole's selective activity against anaerobes, and resistance arises from mutations reducing nitroreductase activity.

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

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