Metronidazole: an update on metabolism, structure-cytotoxicity and resistance mechanisms

Metronidazole, a nitroimidazole, remains a front-line choice for treatment of infections related to inflammatory disorders of the gastrointestinal tract including colitis linked to Clostridium difficile. Despite >60 years of research, the metabolism of metronidazole and associated cytotoxicity is not definitively characterized. Nitroimidazoles are prodrugs that are reductively activated (the nitro group is reduced) under low oxygen tension, leading to imidazole fragmentation and cytotoxicity. It remains unclear if nitroimidazole reduction (activation) contributes to the cytotoxicity profile, or whether subsequent fragmentation of the imidazole ring and formed metabolites alone mediate cytotoxicity. A molecular mechanism underpinning high level (>256 mg/L) bacterial resistance to metronidazole also remains elusive. Considering the widespread use of metronidazole and other nitroimidazoles, this review was undertaken to emphasize the structure-cytotoxicity profile of the numerous metabolites of metronidazole in human and murine models and to examine conflicting reports regarding metabolite-DNA interactions. An alternative hypothesis, that DNA synthesis and repair of existing DNA is indirectly inhibited by metronidazole is proposed. Prokaryotic metabolism of metronidazole is detailed to discuss new resistance mechanisms. Additionally, the review contextualizes the history and current use of metronidazole, rates of metronidazole resistance including metronidazole MDR as well as the biosynthesis of azomycin, the natural precursor of metronidazole. Changes in the gastrointestinal microbiome and the host after metronidazole administration are also reviewed. Finally, novel nitroimidazoles and new antibiotic strategies are discussed.