Centre for Drugs and Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK.
Centre for Drugs and Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK.
Vet Parasitol. 2020 Mar;279:109057. doi: 10.1016/j.vetpar.2020.109057. Epub 2020 Feb 15.
Filarial nematodes are tissue-dwelling parasitic worms that can cause a range of disfiguring pathologies in humans and potentially lethal infections of companion animals. The bacterial endosymbiont, Wolbachia, is present within most human and veterinary filarial pathogens, including the causative agent of heartworm disease, Dirofilaria immitis. Doxycycline-mediated drug targeting of Wolbachia leads to sterility, clearance of microfilariae and gradual death of adult filariae. This mode of action is attractive in the treatment of filariasis because it avoids severe host inflammatory adverse reactions invoked by rapid-killing anthelmintic agents. However, doxycycline needs to be taken for four weeks to exert curative activity. In this review, we discuss the evidence that Wolbachia drug targeting is efficacious in blocking filarial larval development as well as in the treatment of chronic filarial disease. We present the current portfolio of next-generation anti-Wolbachia candidates discovered through phenotypic screening of chemical libraries and validated in a range of in vitro and in vivo filarial infection models. Several novel chemotypes have been identified with selected narrow-spectrum anti-Wolbachia specificity and superior time-to-kill kinetics compared with doxycycline. We discuss the opportunities of developing these novel anti-Wolbachia agents as either cures, adjunct therapies or new preventatives for the treatment of veterinary filariasis.
丝虫是寄生于组织内的寄生蠕虫，可导致人类出现多种致畸形的病理变化，并可能导致伴侣动物感染潜在致命的感染。细菌内共生体沃尔巴克氏体存在于大多数人类和兽医丝虫病原体中，包括心丝虫病的病原体犬恶丝虫。强力霉素介导的沃尔巴克氏体药物靶向作用可导致不育、微丝蚴清除和成虫逐渐死亡。这种作用模式在治疗丝虫病方面很有吸引力，因为它避免了快速杀灭驱虫剂引起的宿主严重炎症不良反应。然而，强力霉素需要服用四周才能发挥治疗作用。在这篇综述中，我们讨论了证据表明，沃尔巴克氏体药物靶向作用在阻止丝虫幼虫发育以及治疗慢性丝虫病方面是有效的。我们介绍了通过化学文库表型筛选发现并在一系列体外和体内丝虫感染模型中得到验证的新一代抗沃尔巴克氏体候选药物。已经确定了几种新型化学型，它们具有与强力霉素相比具有更窄的抗沃尔巴克氏体特异性和更优的杀菌动力学。我们讨论了开发这些新型抗沃尔巴克氏体药物作为兽医丝虫病治疗的治愈药物、辅助治疗药物或新型预防药物的机会。
