Institute of Dental Research and Westmead Centre for Oral Health, Westmead, NSW 2145, Australia.
Department of Life Sciences Faculty of Dentistry, The University of Sydney, NSW 2006, Australia.
J Antimicrob Chemother. 2018 Feb 1;73(2):265-279. doi: 10.1093/jac/dkx351.
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.
甲硝唑是一种硝基咪唑类药物，仍然是治疗与胃肠道炎症性疾病相关感染的一线选择，包括与艰难梭菌相关的结肠炎。尽管已经进行了 >60 年的研究，但甲硝唑的代谢及其相关的细胞毒性仍未得到明确表征。硝基咪唑类药物是前体药物，在低氧张力下被还原激活（硝基被还原），导致咪唑片段断裂和细胞毒性。目前尚不清楚硝基咪唑类药物的还原（激活）是否有助于细胞毒性特征，或者随后咪唑环的断裂和形成的代谢物是否单独介导细胞毒性。高水平（>256mg/L）细菌对甲硝唑耐药的分子机制也仍然难以捉摸。鉴于甲硝唑和其他硝基咪唑类药物的广泛使用，进行了这项综述，以强调甲硝唑在人类和鼠类模型中的众多代谢物的结构-细胞毒性特征，并检查关于代谢物-DNA 相互作用的相互矛盾的报告。提出了一种替代假设，即甲硝唑间接抑制现有 DNA 的合成和修复。详细讨论了甲硝唑的原核代谢，以讨论新的耐药机制。此外，该综述还介绍了甲硝唑的历史和当前用途、包括甲硝唑 MDR 在内的甲硝唑耐药率以及甲硝唑天然前体氮霉素的生物合成。还综述了甲硝唑给药后胃肠道微生物组和宿主的变化。最后，讨论了新型硝基咪唑类药物和新的抗生素策略。
