Abstract：
Cryptosporidiosis is a significant diarrheal disease in humans and animals. Immunodeficient mice are the primary small animal models, but their high costs and specialized breeding/housing requirements limit in vivo drug testing. Numerous anticryptosporidial lead compounds identified in vitro remain untested in vivo.
Cryptosporidium tyzzeri, a natural mouse parasite closely related to Cryptosporidium parvum and Cryptosporidium hominis, was isolated to establish an infection model in immunocompetent mice. The model was validated using classic anticryptosporidial drugs (paromomycin and nitazoxanide) and then employed to assess the efficacy of 3 new leads (vorinostat, docetaxel, and baicalein). An in vitro culture of C. tyzzeri was also developed to complement the animal model.
Chronic C. tyzzeri infection was established in chemically immunosuppressed wild-type mice. Paromomycin (1000 mg/kg/d) and nitazoxanide (100 mg/kg/d) demonstrated efficacy against C. tyzzeri. Vorinostat (30 mg/kg/d), docetaxel (25 mg/kg/d), and baicalein (50 mg/kg/d) were highly effective against C. tyzzeri infection. In vitro, nitazoxanide, vorinostat, docetaxel, and baicalein exhibited low to submicromolar efficacy against C. tyzzeri.
Novel in vivo and in vitro models have been developed for cost-effective anticryptosporidial drug testing. Vorinostat, docetaxel, and baicalein show potential for repurposing and/or optimization for developing new anticryptosporidial drugs.
Cryptosporidium tyzzeri, a natural mouse parasite closely related to Cryptosporidium parvum and Cryptosporidium hominis, was isolated to establish an infection model in immunocompetent mice. The model was validated using classic anticryptosporidial drugs (paromomycin and nitazoxanide) and then employed to assess the efficacy of 3 new leads (vorinostat, docetaxel, and baicalein). An in vitro culture of C. tyzzeri was also developed to complement the animal model.
Chronic C. tyzzeri infection was established in chemically immunosuppressed wild-type mice. Paromomycin (1000 mg/kg/d) and nitazoxanide (100 mg/kg/d) demonstrated efficacy against C. tyzzeri. Vorinostat (30 mg/kg/d), docetaxel (25 mg/kg/d), and baicalein (50 mg/kg/d) were highly effective against C. tyzzeri infection. In vitro, nitazoxanide, vorinostat, docetaxel, and baicalein exhibited low to submicromolar efficacy against C. tyzzeri.
Novel in vivo and in vitro models have been developed for cost-effective anticryptosporidial drug testing. Vorinostat, docetaxel, and baicalein show potential for repurposing and/or optimization for developing new anticryptosporidial drugs.
摘要：
背景：隐孢子虫病是人类和动物的一种重要腹泻病。免疫缺陷小鼠是主要的小动物模型,但是它们的高成本和专门的育种/住房要求限制了体内药物测试。在体外鉴定的许多抗孢子虫先导化合物在体内仍未测试。
方法：隐孢子虫，一种与小隐孢子虫和人隐孢子虫密切相关的天然小鼠寄生虫，分离以建立免疫活性小鼠的感染模型。使用经典的抗孢子虫药物（巴龙霉素和硝唑尼特）对模型进行了验证，然后用于评估3种新导联（伏立诺他，多西他赛,和黄芩苷）。还开发了C.tyzzeri的体外培养以补充动物模型。
结果：在化学免疫抑制的野生型小鼠中建立了慢性C.tyzzeri感染。巴龙霉素(1000mg/kg/d)和硝唑尼特(100mg/kg/d)证明了对抗C.tyzzeri的功效。伏立诺他（30mg/kg/d），多西他赛（25mg/kg/d），黄芩素（50mg/kg/d）对斑竹杆菌感染具有很高的疗效。体外，硝唑尼特，伏立诺他,多西他赛,和黄芩素对C.tyzzeri表现出低至亚微摩尔的功效。
结论：已经开发了新的体内和体外模型，用于经济有效的抗孢子虫药物测试。伏立诺他,多西他赛,和黄芩素显示出再利用和/或优化开发新的抗孢子虫药物的潜力。
方法：隐孢子虫，一种与小隐孢子虫和人隐孢子虫密切相关的天然小鼠寄生虫，分离以建立免疫活性小鼠的感染模型。使用经典的抗孢子虫药物（巴龙霉素和硝唑尼特）对模型进行了验证，然后用于评估3种新导联（伏立诺他，多西他赛,和黄芩苷）。还开发了C.tyzzeri的体外培养以补充动物模型。
结果：在化学免疫抑制的野生型小鼠中建立了慢性C.tyzzeri感染。巴龙霉素(1000mg/kg/d)和硝唑尼特(100mg/kg/d)证明了对抗C.tyzzeri的功效。伏立诺他（30mg/kg/d），多西他赛（25mg/kg/d），黄芩素（50mg/kg/d）对斑竹杆菌感染具有很高的疗效。体外，硝唑尼特，伏立诺他,多西他赛,和黄芩素对C.tyzzeri表现出低至亚微摩尔的功效。
结论：已经开发了新的体内和体外模型，用于经济有效的抗孢子虫药物测试。伏立诺他,多西他赛,和黄芩素显示出再利用和/或优化开发新的抗孢子虫药物的潜力。
