PDF(Pubmed)
Abstract：
OBJECTIVE: Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of antifungal treatment and surgery, although the outcome is frequently disappointing. Therefore, there is a need to identify novel antifungal drugs to treat eumycetoma. In this respect, Medicines for Malaria Venture (MMV) has assembled libraries of compounds for researchers to use in drug discovery research against NTD. Therefore, we screened two MMVOpen compound libraries to identify novel leads for eumycetoma.
METHODS: A total of 400 compounds from the COVID Box and the Global Health Priority Box were screened in vitro at 100 µM and 25 µM against the most common causative agents of eumycetoma, namely Madurella mycetomatis and Falciformispora senegalensis, and the resulting IC50 and MIC50 values were obtained. Compounds with an IC50 < 8 µM were identified for possible in vivo efficacy studies using an M. mycetomatis grain model in Galleria mellonella larvae.
RESULTS: Out of the 400 compounds, 22 were able to inhibit both M. mycetomatis and F. senegalensis growth at 100 µM and 25 µM, with compounds MMV1593278, MMV020335, and MMV1804559 being selected for in vivo testing. Of these three, only the pyrazolopyrimidine derivative MMV1804559 was able to prolong the survival of M. mycetomatis-infected G. mellonella larvae. Furthermore, the grains in MMV1804559-treated larvae were significantly smaller compared to the PBS-treated group.
CONCLUSIONS: MMV1804559 shows promising in vitro and in vivo activity against M. mycetomatis.
METHODS: A total of 400 compounds from the COVID Box and the Global Health Priority Box were screened in vitro at 100 µM and 25 µM against the most common causative agents of eumycetoma, namely Madurella mycetomatis and Falciformispora senegalensis, and the resulting IC50 and MIC50 values were obtained. Compounds with an IC50 < 8 µM were identified for possible in vivo efficacy studies using an M. mycetomatis grain model in Galleria mellonella larvae.
RESULTS: Out of the 400 compounds, 22 were able to inhibit both M. mycetomatis and F. senegalensis growth at 100 µM and 25 µM, with compounds MMV1593278, MMV020335, and MMV1804559 being selected for in vivo testing. Of these three, only the pyrazolopyrimidine derivative MMV1804559 was able to prolong the survival of M. mycetomatis-infected G. mellonella larvae. Furthermore, the grains in MMV1804559-treated larvae were significantly smaller compared to the PBS-treated group.
CONCLUSIONS: MMV1804559 shows promising in vitro and in vivo activity against M. mycetomatis.
摘要：
目的：Eumycetoma是一种被忽视的热带病（NTD），其特征是皮下病变和颗粒形成。治疗Eumycetoma的尝试涉及抗真菌治疗和手术的组合，虽然结果往往令人失望。因此,有必要确定新的抗真菌药物来治疗大肠杆菌瘤。在这方面,疟疾风险药物（MMV）已经组装了化合物库，供研究人员用于针对NTD的药物发现研究。因此,我们筛选了2个MMVOpen化合物文库,以鉴定Eumycetoma的新线索.
方法：在体外筛选了来自COVIDBox和全球健康优先Box的总共400种化合物，分别为100µM和25µM，以对抗最常见的eumycetoma病原体，即白羊座和长尾孢菌，并获得所得的IC50和MIC50值。将IC50<8μM的化合物鉴定为可能的体内功效研究，该研究使用M.mycetomatis谷物模型在Galleriamellonella幼虫中进行。
结果：在400种化合物中，22种能够在100µM和25µM时抑制M.mycetomatis和F.senegalensis的生长，化合物MMV1593278、MMV020335和MMV1804559被选择用于体内测试。在这三个人中,只有吡唑并嘧啶衍生物MMV1804559能够延长M.mycetomatis感染的G.mellonella幼虫的存活。此外，与PBS处理组相比,MMV1804559处理的幼虫的谷粒明显变小.
结论：MMV1804559在体外和体内显示了有希望的抗M.mycetomatis的活性。
方法：在体外筛选了来自COVIDBox和全球健康优先Box的总共400种化合物，分别为100µM和25µM，以对抗最常见的eumycetoma病原体，即白羊座和长尾孢菌，并获得所得的IC50和MIC50值。将IC50<8μM的化合物鉴定为可能的体内功效研究，该研究使用M.mycetomatis谷物模型在Galleriamellonella幼虫中进行。
结果：在400种化合物中，22种能够在100µM和25µM时抑制M.mycetomatis和F.senegalensis的生长，化合物MMV1593278、MMV020335和MMV1804559被选择用于体内测试。在这三个人中,只有吡唑并嘧啶衍生物MMV1804559能够延长M.mycetomatis感染的G.mellonella幼虫的存活。此外，与PBS处理组相比,MMV1804559处理的幼虫的谷粒明显变小.
结论：MMV1804559在体外和体内显示了有希望的抗M.mycetomatis的活性。
