Wilkinson Shane R, Taylor Martin C, Horn David, Kelly John M, Cheeseman Ian
School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, United Kingdom.
Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5022-7. doi: 10.1073/pnas.0711014105. Epub 2008 Mar 26.
Nifurtimox and benznidazole are the front-line drugs used to treat Chagas disease, the most important parasitic infection in the Americas. These agents function as prodrugs and must be activated within the parasite to have trypanocidal effects. Despite >40 years of research, the mechanism(s) of action and resistance have remained elusive. Here, we report that in trypanosomes, both drugs are activated by a NADH-dependent, mitochondrially localized, bacterial-like, type I nitroreductase (NTR), and that down-regulation of this explains how resistance may emerge. Loss of a single copy of this gene in Trypanosoma cruzi, either through in vitro drug selection or by targeted gene deletion, is sufficient to cause significant cross-resistance to a wide range of nitroheterocyclic drugs. In Trypanosoma brucei, loss of a single NTR allele confers similar cross-resistance without affecting growth rate or the ability to establish an infection. This potential for drug resistance by a simple mechanism has important implications, because nifurtimox is currently undergoing phase III clinical trials against African trypanosomiasis.
硝呋替莫和苯硝唑是用于治疗恰加斯病的一线药物，恰加斯病是美洲最重要的寄生虫感染病。这些药物作为前体药物发挥作用，必须在寄生虫体内被激活才能产生杀锥虫作用。尽管经过了40多年的研究，其作用机制和耐药性仍不明确。在此，我们报告在锥虫中，这两种药物均由一种依赖烟酰胺腺嘌呤二核苷酸（NADH）、定位于线粒体、类似细菌的I型硝基还原酶（NTR）激活，而该酶的下调解释了耐药性可能出现的原因。在克氏锥虫中，通过体外药物筛选或靶向基因缺失使该基因的单拷贝缺失，足以导致对多种硝基杂环药物产生显著的交叉耐药性。在布氏锥虫中，单个NTR等位基因的缺失赋予类似的交叉耐药性，而不影响生长速率或建立感染的能力。这种通过简单机制产生耐药性的可能性具有重要意义，因为硝呋替莫目前正在进行针对非洲锥虫病的III期临床试验。
