Strain Prioritization and Genome Mining for Enediyne Natural Products

ABSTRACT The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the...

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Autores principales:	Xiaohui Yan, Huiming Ge, Tingting Huang, Hindra, Dong Yang, Qihui Teng, Ivana Crnovčić, Xiuling Li, Jeffrey D. Rudolf, Jeremy R. Lohman, Yannick Gansemans, Xiangcheng Zhu, Yong Huang, Li-Xing Zhao, Yi Jiang, Filip Van Nieuwerburgh, Christoph Rader, Yanwen Duan, Ben Shen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/179ee3f11bff4e968f30cf7fde3630b7
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spelling	oai:doaj.org-article:179ee3f11bff4e968f30cf7fde3630b72021-11-15T15:50:14ZStrain Prioritization and Genome Mining for Enediyne Natural Products10.1128/mBio.02104-162150-7511https://doaj.org/article/179ee3f11bff4e968f30cf7fde3630b72016-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02104-16https://doaj.org/toc/2150-7511ABSTRACT The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection. IMPORTANCE Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA-approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family.Xiaohui YanHuiming GeTingting HuangHindraDong YangQihui TengIvana CrnovčićXiuling LiJeffrey D. RudolfJeremy R. LohmanYannick GansemansXiangcheng ZhuYong HuangLi-Xing ZhaoYi JiangFilip Van NieuwerburghChristoph RaderYanwen DuanBen ShenAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 6 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Xiaohui Yan Huiming Ge Tingting Huang Hindra Dong Yang Qihui Teng Ivana Crnovčić Xiuling Li Jeffrey D. Rudolf Jeremy R. Lohman Yannick Gansemans Xiangcheng Zhu Yong Huang Li-Xing Zhao Yi Jiang Filip Van Nieuwerburgh Christoph Rader Yanwen Duan Ben Shen Strain Prioritization and Genome Mining for Enediyne Natural Products
description	ABSTRACT The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection. IMPORTANCE Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA-approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family.
format	article
author	Xiaohui Yan Huiming Ge Tingting Huang Hindra Dong Yang Qihui Teng Ivana Crnovčić Xiuling Li Jeffrey D. Rudolf Jeremy R. Lohman Yannick Gansemans Xiangcheng Zhu Yong Huang Li-Xing Zhao Yi Jiang Filip Van Nieuwerburgh Christoph Rader Yanwen Duan Ben Shen
author_facet	Xiaohui Yan Huiming Ge Tingting Huang Hindra Dong Yang Qihui Teng Ivana Crnovčić Xiuling Li Jeffrey D. Rudolf Jeremy R. Lohman Yannick Gansemans Xiangcheng Zhu Yong Huang Li-Xing Zhao Yi Jiang Filip Van Nieuwerburgh Christoph Rader Yanwen Duan Ben Shen
author_sort	Xiaohui Yan
title	Strain Prioritization and Genome Mining for Enediyne Natural Products
title_short	Strain Prioritization and Genome Mining for Enediyne Natural Products
title_full	Strain Prioritization and Genome Mining for Enediyne Natural Products
title_fullStr	Strain Prioritization and Genome Mining for Enediyne Natural Products
title_full_unstemmed	Strain Prioritization and Genome Mining for Enediyne Natural Products
title_sort	strain prioritization and genome mining for enediyne natural products
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/179ee3f11bff4e968f30cf7fde3630b7
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Strain Prioritization and Genome Mining for Enediyne Natural Products

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