title: 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 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.
  
  
  
  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.
authors.affiliation: Department of Chemistry, the Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Chemistry, the Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Huiming
authors.initials: H
authors.lastname: Ge
authors.affiliation: Department of Chemistry, the Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Chemistry, the Scripps Research Institute, Jupiter, Florida, USA.
authors.lastname: Hindra
authors.affiliation: Department of Chemistry, the Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Chemistry, the Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Qihui
authors.initials: Q
authors.lastname: Teng
authors.affiliation: Department of Chemistry, the Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Crnovčić
authors.affiliation: Department of Cancer Biology, the Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Chemistry, the Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rudolf
authors.affiliation: Department of Chemistry, the Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Lohman
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Gansemans
authors.affiliation: Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, China.|Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, Changsha, Hunan, China.
authors.forename: Xiangcheng
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Yunnan Institute of Microbiology, Yunnan University, Kunming, Yunnan, China.
authors.forename: Li-Xing
authors.initials: LX
authors.lastname: Zhao
authors.affiliation: Yunnan Institute of Microbiology, Yunnan University, Kunming, Yunnan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Van Nieuwerburgh
authors.affiliation: Department of Cancer Biology, the Scripps Research Institute, Jupiter, Florida, USA.|Department of Molecular Therapeutics, the Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rader
authors.affiliation: Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, China ywduan66@yahoo.com shenb@scripps.edu.|Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, Changsha, Hunan, China.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Department of Chemistry, the Scripps Research Institute, Jupiter, Florida, USA ywduan66@yahoo.com shenb@scripps.edu.|Department of Molecular Therapeutics, the Scripps Research Institute, Jupiter, Florida, USA.|Natural Products Library Initiative at The Scripps Research Institute, the Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
mesh_terms: D039903:Actinobacteria / Q000737:chemistry* / Q000235:genetics*; D000617:Aminoglycosides / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D045744:Cell Line, Tumor; D055808:Drug Discovery; D053281:Enediynes / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D016680:Genome, Bacterial; D006801:Humans; D010802:Phylogeny; D048630:Polyketide Synthases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D001688:Biological Products; D053281:Enediynes; C058024:C 1027; D048630:Polyketide Synthases