Department of Biosciences and Centre for Global Infectious Diseases, Durham University, Stockton Road, Durham, DH1 3LE, UK.
Glasgow Polyomics, College of Medical, Veterinary & Life Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow, G61 1QH, UK.
Int J Parasitol Drugs Drug Resist. 2019 Dec;11:118-128. doi: 10.1016/j.ijpddr.2019.05.003. Epub 2019 Jun 11.
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.
利什曼病是一种由昆虫媒介传播的原生动物寄生虫利什曼原虫引起的被忽视的热带病。感染影响了世界上最贫穷的数百万人，但目前没有疫苗，药物治疗也很有限。最近，公私合作伙伴关系已经发展起来，以确定控制利什曼病的新方法。这些合作努力大多依赖于行业持有的小分子合成化合物库，但作为抗利什曼病药物被鉴定和进入开发的新化学实体 (NCE) 的数量非常低。有鉴于此，在这里，我们描述了一项公私合作努力，旨在鉴定对导致皮肤利什曼病 (CL) 的利什曼原虫有活性的天然产物。利用 Hypha Discovery 富含小分子 (<500 分子量) 次生代谢物的真菌提取物文库，我们采用迭代表型筛选和分馏方法来鉴定有效的和选择性的抗利什曼原虫化合物。这导致了一种新型氧化倍半萜类化合物的鉴定，该化合物在感染细胞模型中表现出活性，并通过代谢组学方法显示出破坏多种过程的能力。此外，重要的是，这项研究还为 CL 药物发现的新方法奠定了先例。
