Institute of Parasitology, Vetsuisse Faculty, University of Berne, Switzerland.
Parasitology. 2012 Feb;139(2):208-20. doi: 10.1017/S0031182011001776. Epub 2011 Oct 19.
The impact of di-cationic pentamidine-analogues against Toxoplama gondii (Rh- and Me49-background) was investigated. The 72 h-growth assays showed that the arylimidamide DB750 inhibited the proliferation of tachyzoites of T. gondii Rh and T. gondii Me49 with an IC(50) of 0·11 and 0·13 μM, respectively. Pre-incubation of fibroblast monolayers with 1 μM DB750 for 12 h and subsequent culture in the absence of the drug also resulted in a pronounced inhibiton of parasite proliferation. However, upon 5-6 days of drug exposure, T. gondii tachyzoites adapted to the compound and resumed proliferation up to a concentration of 1·2 μM. Out of a set of 32 di-cationic compounds screened for in vitro activity against T. gondii, the arylimidamide DB745, exhibiting an IC(50) of 0·03 μM and favourable selective toxicity was chosen for further studies. DB745 also inhibited the proliferation of DB750-adapted T. gondii (IC(50)=0·07 μM). In contrast to DB750, DB745 also had a profound negative impact on extracellular non-adapted T. gondii tachyzoites, but not on DB750-adapted T. gondii. Adaptation of T. gondii to DB745 (up to a concentration of 0·46 μM) was much more difficult to achieve and feasible only over a period of 110 days. In cultures infected with DB750-adapted T. gondii seemingly intact parasites could occasionally be detected by TEM. This illustrates the astonishing capacity of T. gondii tachyzoites to adapt to environmental changes, at least under in vitro conditions, and suggests that DB745 could be an interesting drug candidate for further assessments in appropriate in vivo models.
研究了二价五聚胍类似物对刚地弓形虫（Rh- 和 Me49-背景）的影响。72 h 生长测定表明，芳基脒 DB750 以 0.11 和 0.13 μM 的 IC50 抑制刚地弓形虫 Rh 和刚地弓形虫 Me49 速殖子的增殖。用 1 μM DB750 预孵育成纤维单层细胞 12 h 并用无药物的培养基继续培养也导致寄生虫增殖的显著抑制。然而，在 5-6 天的药物暴露后，刚地弓形虫速殖子适应了化合物并在高达 1.2 μM 的浓度下恢复增殖。在所筛选的 32 种二价化合物中，对刚地弓形虫具有体外活性的芳基脒 DB745 被选择用于进一步研究，其 IC50 为 0.03 μM，且具有有利的选择性毒性。DB745 也抑制 DB750 适应的刚地弓形虫的增殖（IC50=0.07 μM）。与 DB750 相反，DB745 也对细胞外非适应的刚地弓形虫速殖子具有深远的负面影响，但对 DB750 适应的刚地弓形虫没有影响。刚地弓形虫对 DB745 的适应（最高浓度达 0.46 μM）的难度要大得多，并且只能在 110 天的时间内实现。在感染 DB750 适应的刚地弓形虫的培养物中，通过 TEM 偶尔可以检测到看似完整的寄生虫。这说明了刚地弓形虫速殖子适应环境变化的惊人能力，至少在体外条件下如此，并表明 DB745 可能是进一步在适当的体内模型中评估的一个有趣的候选药物。
