Discovery of an antimalarial compound, burnettiene A, with a multidrug-sensitive Saccharomyces cerevisiae screening system based on mitochondrial function inhibitory activity.

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Accounts of Chemical Research Pub Date : 2024-09-20 DOI:10.1093/bbb/zbae098

Aoi Kimishima, Atsuka Nishitomi, Iori Tsuruoka, Katsuyuki Sakai, Rei Hokari, Masako Honsho, Sota Honma, Yuki Ono, Naozumi Kondo, Hayama Tsutsumi, Yuta Kikuchi, Toshiyuki Tokiwa, Hiroki Kojima, Mayuka Higo, Kenichi Nonaka, Yuki Inahashi, Masato Iwatsuki, Shin-Ichi Fuji, Jun-Pil Jang, Jae-Hyuk Jang, Takumi Chinen, Takeo Usui, Yukihiro Asami

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Abstract

In this paper, we describe our discovery of burnettiene A (1) as an antimalarial compound from the culture broth of Lecanicillium primulinum (current name: Flavocillium primulinum) FKI-6715 strain utilizing our original multidrug-sensitive yeast system. This polyene-decalin polyketide natural product was originally isolated as an antifungal active compound from Aspergillus burnettii. However, the antifungal activity of 1 has been revealed in only one fungal species, and the mechanism of action of 1 remains unknown. After the validation of mitochondrial function inhibitory of 1, we envisioned a new antimalarial drug discovery platform based on mitochondrial function inhibitory activity. We evaluated antimalarial activity and 1 showed antimalarial activity against Plasmodium falciparum FCR3 (chloroquine sensitive) and the K1 strain (chloroquine resistant). Our study revealed the utility of our original screening system based on a multidrug-sensitive yeast and mitochondrial function inhibitory activity for the discovery of new antimalarial drug candidates.

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利用基于线粒体功能抑制活性的多药敏感酿酒酵母筛选系统发现抗疟疾化合物 burnettiene A。

在本文中，我们介绍了利用独创的多药敏感酵母系统，从Lecanicillium primulinum（现名：Flavocillium primulinum）FKI-6715 菌株的培养液中发现的抗疟疾化合物 burnettiene A (1)。这种多烯癸醛多酮天然产物最初是从烧曲霉（Aspergillus burnettii）中分离出来的一种抗真菌活性化合物。然而，目前只在一种真菌中发现了 1 的抗真菌活性，而且 1 的作用机制仍然未知。在对 1 的线粒体功能抑制作用进行验证后，我们设想建立一个基于线粒体功能抑制活性的新型抗疟疾药物发现平台。我们对 1 的抗疟活性进行了评估，结果表明它对恶性疟原虫 FCR3 株（氯喹敏感株）和 K1 株（氯喹耐药株）具有抗疟活性。我们的研究揭示了我们基于多药敏感酵母和线粒体功能抑制活性的原始筛选系统在发现新的抗疟疾候选药物方面的实用性。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.