Kolas Alexandra, Rusman Yudi, Maia Ana C G, Williams Jessica, Fumuso Fernanda G, Cotto-Rosario Alexis, Onoh Chidiebere, Baggar Hanen, Piaskowski Mary L, Baigorria Christian, Paes Raphaella, Chakrabarti Debopam, Weible Lyssa, Ojo Kayode K, O'Connor Roberta M, Salomon Christine E
Department of Veterinary and Biomedical Sciences, University of Minnesota, Minnesota, USA 55108.
Center for Drug Design, University of Minnesota, Minnesota, USA 55455.
bioRxiv. 2025 Jan 3:2025.01.02.631097. doi: 10.1101/2025.01.02.631097.
is a common, waterborne gastrointestinal parasite that causes diarrheal disease worldwide. Currently there are no effective therapeutics to treat cryptosporidiosis in at-risk populations. Since natural products are a known source of anti-parasitic compounds, we screened a library of extracts and pure natural product compounds isolated from bacteria and fungi collected from subterranean environments for activity against . Eight structurally related norditerpene lactones isolated from the fungus collected from the Soudan Iron mine in Minnesota showed potent activity and were further tested to identify the most active compounds. The availability of a diverse suite of natural structural analogs with varying activities allowed us to determine some structure activity relationships for both anti-parasitic activity as well as cytotoxicity. The two most potent compounds, oidiolactones A and B, had ECs against intracellular of 530 and 240 nM respectively without cytotoxicity to confluent HCT-8 host cells. Both compounds also inhibited the related parasite . Oidiolactone A was active against asexual, but not sexual, stages of , and killed 80% of the parasites within 8 hours of treatment. This compound reduced infection by 70% in IFNγ-/- mice, with no signs of toxicity. The high potency, low cytotoxicity, and activity combined with high production, easy isolation from fungi, and synthetic accessibility make oidiolactones A and B attractive scaffolds for the development of new anti- therapeutics.
是一种常见的水源性胃肠道寄生虫，在全球范围内引起腹泻病。目前，尚无有效的疗法来治疗高危人群的隐孢子虫病。由于天然产物是已知的抗寄生虫化合物来源，我们筛选了一个从地下环境收集的细菌和真菌中分离出的提取物和纯天然产物化合物库，以检测其对[寄生虫名称未给出]的活性。从明尼苏达州苏丹铁矿收集的真菌[真菌名称未给出]中分离出的八种结构相关的降二萜内酯显示出强效活性，并进一步进行测试以确定最具活性的化合物。一系列具有不同活性的天然结构类似物的可得性使我们能够确定抗寄生虫活性和细胞毒性的一些构效关系。两种最有效的化合物，oidiolactones A和B，对细胞内[寄生虫名称未给出]的半数有效浓度（EC）分别为530和240 nM，对汇合的HCT-8宿主细胞无细胞毒性。这两种化合物还抑制了相关寄生虫[寄生虫名称未给出]。Oidiolactone A对[寄生虫名称未给出]的无性阶段有活性，但对有性阶段无活性，并且在处理8小时内杀死了80%的寄生虫。该化合物在IFNγ-/-小鼠中使[寄生虫名称未给出]感染减少了70%，且没有毒性迹象。高活性、低细胞毒性以及[具体活性未明确给出]活性，再加上高产量、易于从真菌中分离以及合成可及性，使得oidiolactones A和B成为开发新型抗[寄生虫名称未给出]疗法的有吸引力的骨架。
