Equine Piroplasmosis Laboratory, ICAR-National Research Centre on Equines, Hisar, 125001, Haryana, India; Division of Medicine, Indian Veterinary Research Institute, Bareilly, 243122, Uttar Pradesh, India; Department of Medicine, College of Veterinary Science and Animal Husbandry, Kamdhenu University, Sardarkrushinagar, 385506, Gujarat, India.
Equine Piroplasmosis Laboratory, ICAR-National Research Centre on Equines, Hisar, 125001, Haryana, India; Division of Medicine, Indian Veterinary Research Institute, Bareilly, 243122, Uttar Pradesh, India; Department of Veterinary Clinical Medicine, Madras Veterinary College, TANUVAS, Chennai, 600007, Tamil Naidu, India.
Int J Parasitol Drugs Drug Resist. 2022 Dec;20:11-16. doi: 10.1016/j.ijpddr.2022.07.001. Epub 2022 Jul 30.
Equine piroplasmosis has become a global problem of the equine husbandry sector. Haemoprotozoans evolved very quickly and developed resistance against most of the current available drugs. Phospholipid membrane synthesis by choline kinase enzyme is vital for propagation of intra-erythrocytic protozoa parasites. This pathway was targeted in the present study. Quaternary ammonium salts (QAS) and their analogues act against choline and hamper the biosynthesis process for phosphatidylcholine. We analysed anti-T. equi activity of three QAS - decamethonium bromide (DMB), decyl trimethyl ammonium bromide (DTAB) and dodecyl trimethyl ammonium bromide (DDTAB). Theileria equi parasites in vitro treated with different concentrations of DMB, DDTAB and DTAB. Drug treated T. equi failed to multiply further in the viability test. The IC value of DMB, DDTAB and DTAB for growth inhibition of T. equi was 14.0 μM, 469.51 nM and 558.40 nM, respectively. DMB, DDTAB and DTAB treated T. equi parasites were observed to be devoid of internal structures, showing pyknotic and degenerative appearances. Various concentration of DMB, DDTAB and DTAB were analysed for their cytotoxicity and haemolytic activity on horse's PBMCs and RBCs. DMB was less than 10% cytotoxic to PBMCs, while DDTAB and DTAB were 40%-50% cytotoxic at 1000 μM concentrations. The respective CC values were 7202.96 μM, 1026.26 μM and 1263.95 μM. DMB and DTAB showed least haemolytic activity (<3%); whereas DDTAB was more haemolytic to RBCs at highest concentration of 2000 μM. The respective CC values of these drugs were 224495.3 μM, and 39101.35 μM; 713.54 μM. Specific selective index for DMB, DDTAB and DTAB values with respect to host's PBMC and RBC cells, were 514.50, 2185.81, 2263.52 and 16035.38, 1519.75, 70023.91, respectively. These data indicated its non-toxicity to host's cells and selective potential of anti-T. equi in vitro activity.
马梨形虫病已成为马业的全球性问题。血液原生动物进化非常迅速，并对大多数现有药物产生了耐药性。胆碱激酶酶的磷脂膜合成对于红细胞内原生动物寄生虫的繁殖至关重要。本研究针对该途径。季铵盐（QAS）及其类似物针对胆碱并阻碍磷脂酰胆碱的生物合成过程。我们分析了三种 QAS-癸甲溴铵（DMB）、十一烷基三甲基溴化铵（DTAB）和十二烷基三甲基溴化铵（DDTAB）对马媾疫锥虫（T. equi）的抗活力。用不同浓度的 DMB、DDTAB 和 DTAB 体外处理 T. equi 寄生虫。药物处理的 T. equi 在活力测试中未能进一步繁殖。DMB、DDTAB 和 DTAB 对 T. equi 生长抑制的 IC 值分别为 14.0μM、469.51nM 和 558.40nM。用 DMB、DDTAB 和 DTAB 处理的 T. equi 寄生虫被观察到没有内部结构，呈现出固缩和退行性外观。分析了不同浓度的 DMB、DDTAB 和 DTAB 对马外周血单核细胞（PBMCs）和红细胞（RBCs）的细胞毒性和溶血活性。DMB 对 PBMCs 的细胞毒性小于 10%，而 DDTAB 和 DTAB 在 1000μM 浓度时的细胞毒性为 40%-50%。相应的 CC 值分别为 7202.96μM、1026.26μM 和 1263.95μM。DMB 和 DTAB 显示出最小的溶血活性（<3%）；而 DDTAB 在 2000μM 的最高浓度下对 RBCs 更具溶血作用。这些药物的相应 CC 值分别为 224495.3μM、39101.35μM 和 713.54μM。DMB、DDTAB 和 DTAB 相对于宿主 PBMC 和 RBC 细胞的特异性选择指数值分别为 514.50、2185.81、2263.52 和 16035.38、1519.75、70023.91。这些数据表明它对宿主细胞无毒，并且具有体外抗 T. equi 的选择性潜力。
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