Strain Prioritization and Genome Mining for Enediyne Natural Products

• DOI: 10.1128/mbio.02104-16
• Publication Date: 2016-12-23T18:48:16Z
• Authors: 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 Nieuwer...; Christoph Rader; Yanwen Duan; Ben Shen
• Keywords: Enediyne; Comparative Genomics

ABSTRACT The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, yet only 11 enediynes have been structurally characterized to date. Here we report genome survey 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the polyketide synthase cassettes could be grouped into 28 distinct clades based phylogenetic analysis. Genome sequencing 31 representative confirmed each clade harbors biosynthetic gene cluster. A neighborhood network allows prediction new structural features insights exploited for discovery. We one as C-1027 producers, with significantly higher titer than original producer, discovered products, tiancimycins (TNMs), exhibit potent cytotoxicity against broad spectrum cancer cell lines. Our results demonstrate feasibility rapid discovery from large strain collection. IMPORTANCE Recent advances in microbial genomics clearly revealed potential soil actinomycetes produce is underappreciated. great challenge develop innovative methods discover them sufficient quantities chemical, biological, clinical investigations. This work demonstrated will practical supply this important drug lead. TNMs, their extremely various cells complete killing characteristics, comparison payloads used FDA-approved antibody-drug conjugates (ADCs), are poised payload candidates next generation anticancer ADCs. Follow-up studies other identified hits promise enediynes, radically expanding chemical space family.