Li Hang, Ji Shengwei, Ariefta Nanang R, Galon Eloiza May S, El-Sayed Shimaa A E S, Do Thom, Jia Lijun, Sakaguchi Miako, Asada Masahito, Nishikawa Yoshifumi, Qin Xin, Liu Mingming, Xuan Xuenan
National Research Center for Protozoan Diseases, Obihiro University of Agriculture Veterinary Medicine, Obihiro, Japan.
Department of Veterinary Medicine, Agriculture College of Yanbian University, Yanji, China.
Elife. 2025 Jun 19;13:RP101128. doi: 10.7554/eLife.101128.
Babesiosis is a disease brought on by intraerythrocytic parasites of the genus . Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs against . Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainly and . This study evaluated the growth-inhibiting properties of CIP against spp. and investigated the mechanism of CIP on . The half inhibitory concentration (IC) values of CIP against the in vitro growth of and were 20.2 ± 1.4 and 69.4 ± 2.2 nM, respectively. CIP significantly inhibited the growth of and in vivo. Resistance was conferred by L921V and L921I mutations in BgATP4, which reduced the sensitivity to CIP by 6.1- and 12.8-fold. The inhibitory potency of CIP against BgATP4-associated ATPase activity was moderately reduced in mutant strains, with a 1.3- and 2.4-fold decrease in BgATP4 and BgATP4, respectively, compared to that of BgATP4. An in silico investigation revealed reductions in affinity for CIP binding to BgATP4 and BgATP4 compared to BgATP4. Resistant strains showed no significant cross-resistance to atovaquone or tafenoquine succinate (TQ), with less than a onefold change in IC values. Combining CIP with TQ effectively eliminated infection in SCID mice with no relapse, and parasite DNA was not detected by qPCR within 90 days post-infection. Our findings reveal the efficacy of CIP as an antibabesial agent, its limitations as a monotherapy due to resistance development, and the potential of combination therapy with TQ to overcome said resistance and achieve complete parasite clearance.
巴贝斯虫病是由巴贝斯属的红细胞内寄生虫引起的一种疾病。目前的化疗伴有副作用且寄生虫会复发。因此，开发针对巴贝斯虫的高效药物至关重要。西帕加明（CIP）已显示出对顶复门寄生虫有抑制作用，主要是疟原虫和弓形虫。本研究评估了CIP对巴贝斯虫属物种的生长抑制特性，并研究了CIP对巴贝斯虫的作用机制。CIP对体外培养的牛巴贝斯虫和双芽巴贝斯虫生长的半数抑制浓度（IC）值分别为20.2±1.4 nM和69.4±2.2 nM。CIP在体内显著抑制了牛巴贝斯虫和双芽巴贝斯虫的生长。BgATP4中的L921V和L921I突变赋予了耐药性，这使对CIP的敏感性降低了6.1倍和12.8倍。与野生型BgATP4相比，突变株中CIP对BgATP4相关ATP酶活性的抑制效力适度降低，BgATP4和BgATP4分别降低了1.3倍和2.4倍。计算机模拟研究表明，与BgATP4相比，CIP与BgATP4和BgATP4的结合亲和力降低。耐药菌株对阿托伐醌或琥珀酸tafenoquine（TQ）没有明显的交叉耐药性，IC值变化小于1倍。将CIP与TQ联合使用可有效消除SCID小鼠体内的巴贝斯虫感染且无复发，感染后90天内通过qPCR未检测到寄生虫DNA。我们的研究结果揭示了CIP作为抗巴贝斯虫药物的疗效、由于耐药性发展导致其作为单一疗法的局限性，以及与TQ联合治疗克服所述耐药性并实现完全清除寄生虫的潜力。
