Nakamura Ikuko, Kanasaki Ryuichi, Yoshikawa Koji, Furukawa Shigetada, Fujie Akihiko, Hamamoto Hiroshi, Sekimizu Kazuhisa
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Teikyo University Institute of Medical Mycology, Tokyo, Japan.
J Antibiot (Tokyo). 2017 Jan;70(1):41-44. doi: 10.1038/ja.2016.106. Epub 2016 Aug 31.
Natural products are the major source of currently available drugs. However, screening natural product presents several challenges, including the time-consuming and labor-intensive steps required for the isolation of a drug from crude extracts as well as the differences between the activities of compounds in vitro and in vivo. To address these challenges, we used silkworm larvae infected with Aspergillus fumigatus to screen a natural products library for potent drugs to treat invasive aspergillosis. A rationally designed library was constructed using numerous, geographically diverse fungal species and then screened to collect extracts of microorganisms that had detectable anti-Aspergillus activity. We evaluated this library using cultures of A. fumigatus and a silkworm model system of A. fumigatus infection. With this model, we identified the novel antifungal compound ASP2397 that not only cured infected silkworm larvae but also increased the rates of survival of mice infected with A. fumigatus. These findings strongly support the utility of the silkworm screening system for the simple and rapid isolation of antibiotics from natural products libraries.
天然产物是目前可用药物的主要来源。然而，筛选天然产物存在若干挑战，包括从粗提物中分离药物所需的耗时且费力的步骤，以及化合物体外和体内活性的差异。为应对这些挑战，我们利用感染烟曲霉的家蚕幼虫来筛选天然产物文库，以寻找治疗侵袭性曲霉病的有效药物。使用多种地理来源不同的真菌构建了一个经过合理设计的文库，然后进行筛选，收集具有可检测到的抗曲霉活性的微生物提取物。我们使用烟曲霉培养物和烟曲霉感染的家蚕模型系统对该文库进行了评估。通过这个模型，我们鉴定出了新型抗真菌化合物ASP2397，它不仅治愈了受感染的家蚕幼虫，还提高了感染烟曲霉的小鼠的存活率。这些发现有力地支持了家蚕筛选系统在从天然产物文库中简单快速分离抗生素方面的实用性。
