The new anthelmintic tribendimidine is an L-type (levamisole and pyrantel) nicotinic acetylcholine receptor agonist.
The new anthelmintic tribendimidine is an L-type (levamisole and pyrantel) nicotinic acetylcholine receptor agonist.
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DOI：
10.1371/journal.pntd.0000499
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发表时间：
2009-08-11
影响因子：
3.8
通讯作者：
Aroian RV
中科院分区：
文献类型：
--
作者：
Hu Y;Xiao SH;Aroian RV
肠道寄生线虫，如钩虫、蛔虫和鞭虫是当今世界上最流行的热带寄生虫。虽然这些寄生虫造成了巨大的疾病负担，但我们几乎没有驱虫药来治疗它们。在过去的三十年里，只有一种新的驱虫剂--三苯二胺--被开发出来，并进入了人体临床试验。研究表明，三苯二胺是安全的，对蛔虫和钩虫具有良好的临床活性。然而，目前对其作用机制和潜在的耐药途径知之甚少(S)。这些信息对于预防、检测和管理耐药性、安全考虑以及了解如何将三苯二胺与其他驱虫药结合是很重要的。为了研究三苯二胺是如何起作用的，以及对它的抗药性可能是如何产生的，我们转向了遗传上容易驯化的线虫--秀丽线虫。当接触到三苯二胺时，线虫两性人几乎立即失去运动能力；长期接触会导致广泛的身体损害、发育停滞、生殖力下降和/或死亡。我们对三苯二胺抗性突变体进行了正向遗传筛选，获得了10个抗性等位基因，它们属于四个互补组。中毒试验、互补试验、基因图谱试验和核酸测序表明，三苯二胺耐药突变株也对左旋咪唑和吡喃酮耐药，并改变了突变为左旋咪唑耐药的相同基因。此外，我们还证明了基于对左旋咪唑的抗性而分离的11个线虫突变体也对三苯二胺具有耐药性。结果表明，三苯二胺对线虫的作用机制与左旋咪唑和吡喃酮相同，即三苯二胺是L亚型的nAChR激动剂。因此，在对左旋咪唑或吡喃酮已经产生抗药性的地方，三苯二胺可能不是一种可行的驱虫剂，但在对苯并咪唑存在抗药性的地方可以有效地使用，或者可以与这类驱虫剂结合使用。在热带国家，肠道寄生线虫或蛔虫感染了超过10亿人。总体而言，它们是包括儿童和孕妇在内的感染者发病的一个巨大来源，越来越多地被认为是促进贫困的关键寄生虫。尽管它们很重要，但处理它们的药物却很少。此外，没有一种具有最佳疗效，所有寄生虫都可以抵抗，而且由于实际原因，只有一种用于单剂量大规模药物管理(MDA)。迫切需要更好的蛔虫药物(驱虫药)。在过去的30年里，只有一种由中国疾控中心开发的驱虫药--三苯二胺--进入了人体临床试验。三苯二胺对某些蛔虫有较好的单次给药效果。然而，三苯二胺是如何起作用的还不清楚。在这里，我们使用秀丽隐杆线虫在实验室中进化出对三苯二胺的抗药性，随后进行了遗传和分子测试以及交叉耐药性药物研究，我们证明了三苯二胺与两种已知的驱虫药左旋咪唑和吡喃酮明确属于同一药物家族。这些结果对于如何在已知或怀疑对当前药物产生耐药性的MDA中使用三苯二胺，以及如何将三苯二胺与其他药物联合使用，以最大限度地提高治疗效果，同时将耐药性威胁降至最低，具有重要的意义。
Intestinal parasitic nematodes such as hookworms, Ascaris lumbricoides, and Trichuris trichiura are amongst most prevalent tropical parasites in the world today. Although these parasites cause a tremendous disease burden, we have very few anthelmintic drugs with which to treat them. In the past three decades only one new anthelmintic, tribendimidine, has been developed and taken into human clinical trials. Studies show that tribendimidine is safe and has good clinical activity against Ascaris and hookworms. However, little is known about its mechanism of action and potential resistance pathway(s). Such information is important for preventing, detecting, and managing resistance, for safety considerations, and for knowing how to combine tribendimidine with other anthelmintics. To investigate how tribendimidine works and how resistance to it might develop, we turned to the genetically tractable nematode, Caenorhabditis elegans. When exposed to tribendimidine, C. elegans hermaphrodites undergo a near immediate loss of motility; longer exposure results in extensive body damage, developmental arrest, reductions in fecundity, and/or death. We performed a forward genetic screen for tribendimidine-resistant mutants and obtained ten resistant alleles that fall into four complementation groups. Intoxication assays, complementation tests, genetic mapping experiments, and sequencing of nucleic acids indicate tribendimidine-resistant mutants are resistant also to levamisole and pyrantel and alter the same genes that mutate to levamisole resistance. Furthermore, we demonstrate that eleven C. elegans mutants isolated based on their ability to resist levamisole are also resistant to tribendimidine. Our results demonstrate that the mechanism of action of tribendimidine against nematodes is the same as levamisole and pyrantel, namely, tribendimidine is an L-subtype nAChR agonist. Thus, tribendimidine may not be a viable anthelmintic where resistance to levamisole or pyrantel already exists but could productively be used where resistance to benzimidazoles exists or could be combined with this class of anthelmintics. Intestinal parasitic nematodes or roundworms infect over 1 billion people in tropical countries. Overall, they are a huge source of morbidity in infected people, including children and pregnant women, and are increasingly being recognized as key poverty-promoting parasites. Despite their importance, few drugs for dealing with them exist. Furthermore, none has optimal efficacy, all can be resisted by the parasites, and, for practical reasons, only one is used for single-dose Mass Drug Administrations (MDAs). There is a dire need for better roundworm drugs (anthelmintics). In the past 30 years, only one anthelmintic, tribendimidine, developed by the Chinese CDC, has entered human clinical trials. Tribendimidine has good single-dose efficacy against some roundworm parasites. However, how tribendimidine works was unknown. Here, using the roundworm Caenorhabditis elegans to evolve resistance to tribendimidine in the lab, followed by genetic and molecular testing and cross-resistance drug studies, we demonstrate that tribendimidine is unequivocally in the same drug family as two known anthelmintics, levamisole and pyrantel. These results have important implications for how tribendimidine might be used in MDAs where resistance to current drugs is known or suspected and for how tribendimidine might be combined with other drugs to maximize therapy while minimizing resistance threats.
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