奥罗霉素：通过CRISPR-Cas9激活从玫瑰孢链霉菌中获得的一种强效抗生素。

Auroramycin: A Potent Antibiotic from Streptomyces roseosporus by CRISPR-Cas9 Activation.

作者信息

Lim Yee Hwee, Wong Fong Tian, Yeo Wan Lin, Ching Kuan Chieh, Lim Yi Wee, Heng Elena, Chen Shuwen, Tsai De-Juin, Lauderdale Tsai-Ling, Shia Kak-Shan, Ho Ying Swan, Hoon Shawn, Ang Ee Lui, Zhang Mingzi M, Zhao Huimin

机构信息

Organic Chemistry, Institute of Chemical and Engineering Sciences (ICES), A*STAR, 8 Biomedical Grove, Neuros #07-01/02/03, Singapore, 138665, Singapore.

Molecular Engineering Lab (MEL), Biomedical Science Institutes, A*STAR, 61 Biopolis Drive, Proteos #13-02, Singapore, 138673, Singapore.

出版信息

Chembiochem. 2018 May 25. doi: 10.1002/cbic.201800266.

DOI:10.1002/cbic.201800266

PMID:29799651

Abstract

Silent biosynthetic gene clusters represent a potentially rich source of new bioactive compounds. We report the discovery, characterization, and biosynthesis of a novel doubly glycosylated 24-membered polyene macrolactam from a silent biosynthetic gene cluster in Streptomyces roseosporus by using the CRISPR-Cas9 gene cluster activation strategy. Structural characterization of this polyketide, named auroramycin, revealed a rare isobutyrylmalonyl extender unit and a unique pair of amino sugars. Relative and absolute stereochemistry were determined by using a combination of spectroscopic analyses, chemical derivatization, and computational analysis. The activated gene cluster for auroramycin production was also verified by transcriptional analyses and gene deletions. Finally, auroramycin exhibited potent anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity towards clinical drug-resistant isolates.

摘要

沉默的生物合成基因簇是新型生物活性化合物的潜在丰富来源。我们报告了通过使用CRISPR-Cas9基因簇激活策略，从玫瑰孢链霉菌中一个沉默的生物合成基因簇中发现、表征和生物合成一种新型双糖基化的24元多烯大环内酰胺。这种聚酮化合物名为极光霉素，其结构表征揭示了一个罕见的异丁酰丙二酰延伸单元和一对独特的氨基糖。通过光谱分析、化学衍生化和计算分析相结合的方法确定了相对和绝对立体化学。通过转录分析和基因缺失也验证了用于生产极光霉素的激活基因簇。最后，极光霉素对临床耐药菌株表现出强大的抗耐甲氧西林金黄色葡萄球菌（抗MRSA）活性。