Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the World's poorest, however vaccines are absent and drug therapy limited. Recently, public-private partnerships have developed to identify new modes of controlling leishmaniasis. Most of these collaborative efforts have relied upon the small molecule synthetic compound libraries held by industry, but the number of New Chemical Entities (NCE) identified and entering development as antileishmanials has been very low. In light of this, here we describe a public-private effort to identify natural products with activity against Leishmania mexicana, a causative agent of cutaneous leishmanaisis (CL). Utilising Hypha Discovery's fungal extract library which is rich in small molecule (<500 molecular weight) secondary metabolites, we undertook an iterative phenotypic screening and fractionation approach to identify potent and selective antileishmanial hits. This led to the identification of a novel oxidised bisabolane sesquiterpene which demonstrated activity in an infected cell model and was shown to disrupt multiple processes using a metabolomic approach. In addition, and importantly, this study also sets a precedent for new approaches for CL drug discovery.

中文翻译：

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在真菌提取物库中开采天然产物抗真菌药。

利什曼病是由昆虫媒介传播的原生动物寄生虫利什曼原虫种引起的被忽视的热带病。感染影响了世界上数以百万计的最贫困人口，但是缺少疫苗并且药物治疗受到限制。最近，已经建立了公私合作伙伴关系，以确定控制利什曼病的新模式。这些合作中的大多数都依赖于工业界拥有的小分子合成化合物库，但是已被识别并进入开发阶段的新化学实体（NCE）的数量非常少。有鉴于此，我们在此描述了一种公私合营的努力，以鉴定具有抗墨西哥利什曼原虫（皮肤利什曼病（CL）的病原体）活性的天然产物。利用富含小分子的Hypha Discovery真菌提取物文库（< 分子量为500的次级代谢产物），我们采用了迭代表型筛选和分级分离方法来鉴定有效的和选择性的抗疟疾药物。这导致鉴定出一种新的氧化的双倍半脂倍半萜烯，其在感染的细胞模型中表现出活性，并显示出通过代谢组学方法破坏了多个过程。此外，重要的是，这项研究还为CL药物发现的新方法树立了先例。