Discovery of an Antibacterial Isoindolinone-Containing Tetracyclic Polyketide by Cryptic Gene Activation and Characterization of Its Biosynthetic Gene Cluster,ACS Chemical Biology

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Discovery of an Antibacterial Isoindolinone-Containing Tetracyclic Polyketide by Cryptic Gene Activation and Characterization of Its Biosynthetic Gene Cluster
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-08-06 00:00:00 , DOI: 10.1021/acschembio.8b00553
Wei Li Thong , Kazuo Shin-ya ₁ , Makoto Nishiyama , Tomohisa Kuzuyama

Affiliation

The major setback in natural product screening is the decreasing hit rate of novel bioactive compounds containing new chemical skeletons. Here we report the identification and biosynthesis of isoindolinomycin (Idm), an unprecedented bioactive polyketide with a novel isoindolinone-containing tetracyclic skeleton. Idm was discovered through the screening of rifampicin-resistant (rif) mutants that were generated from nine actinomycete strains used in this study. Of the 114 rif mutants isolated, the mutant S55-50-5 was found to overproduce Idm, which is almost undetectable in the wild-type Streptomyces sp. SoC090715LN-16. An in silico analysis coupled with gene deletion experiments revealed a biosynthetic idmB gene cluster that is responsible for the production of Idm. The biosynthetic studies of Idm primarily focused on the formation of the five-membered ring in the tetracyclic structure and the attachment of the methyl group to the core structure. In addition, a malachite green phosphate assay performed using a stand-alone adenylation domain (idmB21) demonstrated the involvement of glycine in the formation of the isoindolinone-containing skeleton. This study contributes to an increase in the structural diversity of polyketides and paves the way toward an understanding of the complete biosynthetic pathway of a novel class of tetracyclic polyketides.

中文翻译：

通过隐秘基因激活及其生物合成基因簇的表征发现一种含异吲哚啉酮的抗菌四环聚酮

天然产物筛选的主要障碍是含有新化学骨架的新型生物活性化合物的命中率不断降低。在这里，我们报告的鉴定和生物合成的异靛霉素（Idm），一种具有新型的含异吲哚啉酮的四环骨架的前所未有的生物活性聚酮化合物。Idm是通过筛选耐利福平（rif）突变体而发现的，该突变体是从本研究中使用的九种放线菌菌株中产生的。在分离出的114个rif突变体中，发现突变体S55-50-5过量生产Idm，这在野生型链霉菌sp。中几乎无法检测到。SoC090715LN-16。一个在硅片加上基因缺失实验分析显示生物合成idmB负责Idm产生的基因簇。Idm的生物合成研究主要集中在四环结构中五元环的形成以及甲基与核心结构的连接上。此外，使用独立的腺苷酸化结构域（idmB21）进行的孔雀石绿色磷酸盐检测证明甘氨酸参与了含异吲哚啉酮骨架的形成。这项研究有助于增加聚酮化合物的结构多样性，并为理解新型一类四环聚酮化合物的完整生物合成途径铺平了道路。

更新日期：2018-08-06

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