Macrocyclic lactones are front-line therapies for parasitic roundworm infections, but there are no comprehensive studies on the activity of this drug class against parasitic flatworms. Ivermectin is well known to be inactive against flatworms. However, the structure-activity relationship of macrocyclic lactones may vary across phyla, and it is entirely possible other members of this drug class do in fact show antiparasitic activity on flatworms. For example, there are several reports hinting at the anti-schistosomal activity of doramectin and moxidectin. To explore this class further, we developed an automated imaging assay combined with measurement of lactate levels from worm media. This assay was applied to the screening of 21 macrocyclic lactones (avermectins, milbemycins and others such as spinosyns) against adult schistosomes. These in vitro assays identified several macrocyclic lactones (emamectin, milbemycin oxime, and the moxidectin metabolite 23-ketonemadectin) that caused contractile paralysis and lack of lactate production. Several of these were also active against miracidia, a juvenile life cycle stage of the parasite. Hits prioritized from these in vitro assays were administered to mice harboring patent schistosome infections. However, no reduction in worm burden was observed. Nevertheless, these data show the utility of a multiplexed in vitro screening platform to quantitatively assess drug action and prioritize hits in a chemical series for in vivo studies. While the prototypical macrocyclic lactone ivermectin displays minimal activity against adult Schistosoma mansoni, this family of compounds does contain schistocidal compounds which may serve as a starting point for development of new anti-flatworm chemotherapies.

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大环内酯对寄生血吸虫扁虫的表型分析

大环内酯是寄生虫蛔虫感染的一线治疗药物，但尚无关于该类药物对寄生虫扁虫的活性的综合研究。众所周知，伊维菌素对扁虫没有活性。然而，大环内酯的构效关系可能因门而异，而且这一类药物的其他成员完全有可能实际上对扁虫表现出抗寄生虫活性。例如，有几篇报道暗示了多拉菌素和莫昔克丁的抗血吸虫活性。为了进一步探索这一类，我们开发了一种自动成像测定，并结合了蠕虫培养基中乳酸水平的测量。该测定法用于筛选针对成人血吸虫的 21 种大环内酯（阿维菌素、米尔倍霉素和其他如多杀菌素）。这些体外试验确定了几种大环内酯（阿维菌素、米尔倍霉素肟和莫昔克丁代谢物 23-酮甲菌素），它们会导致收缩麻痹和乳酸生成不足。其中一些还对毛蚴病有效，这是寄生虫的幼年生命周期阶段。从这些体外试验中优先获得的命中结果被施用于患有明显血吸虫感染的小鼠。然而，没有观察到蠕虫负担的减少。尽管如此，这些数据显示了多重体外筛选平台在定量评估药物作用和优先考虑化学系列中的命中以进行体内研究方面的效用。虽然原型大环内酯伊维菌素对成人的活性很小曼氏血吸虫，这个化合物家族确实含有杀血吸虫化合物，可以作为开发新的抗扁虫化学疗法的起点。