Institute of Parasitology, Vetsuisse Faculty, Department of Infectious Diseases and Pathobiology, University of Bern, Länggass-Strasse 122, 3012 Bern, Switzerland.
Graduate School for Cellular and Biomedical Sciences, University of Bern, Mittelstrasse 43, 3012 Bern, Switzerland.
Molecules. 2021 Oct 22;26(21):6393. doi: 10.3390/molecules26216393.
The quinolone decoquinate (DCQ) is widely used in veterinary practice for the treatment of bacterial and parasitic infections, most notably, coccidiosis in poultry and in ruminants. We have investigated the effects of treatment of in infected human foreskin fibroblasts (HFF) with DCQ. This induced distinct alterations in the parasite mitochondrion within 24 h, which persisted even after long-term (500 nM, 52 days) treatment, although there was no parasiticidal effect. Based on the low half-maximal effective concentration (IC) of 1.1 nM and the high selectivity index of >5000, the efficacy of oral treatment of pregnant mice experimentally infected with oocysts with DCQ at 10 mg/kg/day for 5 days was assessed. However, the treatment had detrimental effects, induced higher neonatal mortality than infection alone, and did not prevent vertical transmission. Thus, three quinoline--carbamate derivatives of DCQ, anticipated to have better physicochemical properties than DCQ, were assessed in vitro. One such compound, RMB060, displayed an exceedingly low IC of 0.07 nM, when applied concomitantly with the infection of host cells and had no impact on HFF viability at 10 µM. As was the case for DCQ, RMB060 treatment resulted in the alteration of the mitochondrial matrix and loss of cristae, but the changes became apparent at just 6 h after the commencement of treatment. After 48 h, RMB060 induced the expression of the bradyzoite antigen BAG1, but TEM did not reveal any other features reminiscent of bradyzoites. The exposure of infected cultures to 300 nM RMB060 for 52 days did not result in the complete killing of all tachyzoites, although mitochondria remained ultrastructurally damaged and there was a slower proliferation rate. The treatment of mice infected with oocysts with RMB060 did reduce parasite burden in non-pregnant mice and dams, but vertical transmission to pups could not be prevented.
地克珠利（DCQ）在兽医实践中被广泛用于治疗细菌和寄生虫感染，最著名的是家禽和反刍动物的球虫病。我们研究了用 DCQ 治疗感染的人包皮成纤维细胞（HFF）中的效果。这在 24 小时内就导致了寄生虫线粒体的明显改变，即使经过长期（500 nM，52 天）治疗后仍持续存在，尽管没有寄生虫杀灭作用。基于低半最大有效浓度（IC）为 1.1 nM 和 >5000 的高选择性指数，评估了口服治疗感染 的实验感染孕鼠的疗效，每日 10mg/kg，连续 5 天。然而，这种治疗方法有不良影响，导致新生儿死亡率高于单纯感染，并且不能阻止垂直传播。因此，评估了地克珠利的三种喹啉-氨基甲酸酯衍生物，预期其理化性质优于地克珠利。其中一种化合物 RMB060，当与宿主细胞感染同时应用时，其 IC 非常低，为 0.07 nM，在 10 µM 时对 HFF 存活率没有影响。与地克珠利一样，RMB060 处理导致线粒体基质和嵴的改变，但在开始治疗后仅 6 小时就变得明显。48 小时后，RMB060 诱导了缓殖子抗原 BAG1 的表达，但 TEM 没有显示出任何其他类似于缓殖子的特征。用 300 nM RMB060 暴露感染培养物 52 天不会导致所有速殖子完全被杀灭，尽管线粒体仍然超微结构受损，增殖速度较慢。用 RMB060 治疗感染的卵囊小鼠可减少非怀孕小鼠和母鼠中的寄生虫负担，但不能防止垂直传播给幼鼠。
