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.

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新型抗沃尔巴克氏菌药物，治疗和预防兽用丝虫病的新方法？

丝虫线虫是寄生在组织中的蠕虫，可导致人类出现一系列毁容性病变，并可能对伴侣动物造成致命感染。细菌内共生体 Wolbachia 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 Wolbachia 药物靶向导致不育、清除微丝蚴和成虫逐渐死亡。这种作用方式在治疗丝虫病方面很有吸引力，因为它避免了由快速杀虫剂引起的严重宿主炎症不良反应。然而，强力霉素需要服用四个星期才能发挥疗效。在这次审查中，我们讨论了 Wolbachia 药物靶向在阻断丝虫幼虫发育以及治疗慢性丝虫病方面有效的证据。我们展示了目前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验证的下一代抗沃尔巴克氏体候选物的组合。与强力霉素相比，已经确定了几种新的化学型，具有选定的窄谱抗沃尔巴克氏菌特异性和优越的杀灭时间动力学。我们讨论了开发这些新型抗沃尔巴克氏菌药物作为治疗兽用丝虫病的治疗方法、辅助疗法或新预防剂的机会。我们展示了目前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验证的下一代抗沃尔巴克氏体候选物的组合。与强力霉素相比，已经确定了几种新的化学型，具有选定的窄谱抗沃尔巴克氏菌特异性和优越的杀灭时间动力学。我们讨论了开发这些新型抗沃尔巴克氏菌药物作为治疗兽用丝虫病的治疗方法、辅助疗法或新预防剂的机会。我们展示了目前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验证的下一代抗沃尔巴克氏体候选物的组合。与强力霉素相比，已经确定了几种新的化学型，具有选定的窄谱抗沃尔巴克氏菌特异性和优越的杀灭时间动力学。我们讨论了开发这些新型抗沃尔巴克氏菌药物作为治疗兽用丝虫病的治疗方法、辅助疗法或新预防剂的机会。