Abstract
ABSTRACTThe 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.
Highlights
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
A great challenge is that of developing innovative methods to discover new enediynes and producing them in sufficient quantities for chemical, biological, and clinical investigations
Comparative analysis of the 10 gene clusters revealed a set of 5 genes common to all enediynes, i.e., the enediyne polyketide synthase (PKS) gene cassette consisting of E3, E4, E5, E, and E10 (E3/E4/E5/E/E10) (Fig. S2A) [17, 20,21,22]; no apparent conservation was observed beyond the enediyne PKS gene cassettes, accounting for the structural diversity characteristic for the periphery moieties of the enediynes (Fig. S1A and B)
Summary
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. When positioned within the minor groove of DNA, the diradical abstracts hydrogen atoms from the deoxyribose backbone of duplex DNA; the DNA-centered radicals can cause interstrand cross-links (ICLs) or react with molecular oxygen, leading to DNA double-strand breaks (DSBs), or both [3, 4, 7, 8] With their exquisite mode of action and their extraordinary cytotoxicity, the enediynes have been successfully translated into clinical drugs. To demonstrate the feasibility of our approach in rapidly discovering new enediynes from a large strain collection, we characterized a new C-1027 producer with a significantly higher C-1027 titer than the original Streptomyces globisporus producer [9, 10] and discovered the tiancimycins (TNMs), new enediyne natural products that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines and kill selected cancer cells more rapidly and completely than the payloads used in FDA-approved antibody (Ab)-drug conjugates (ADCs). Production of TNMs in sufficient quantities by microbial fermentation and manipulation of TNM biosynthesis for engineering new analogues were demonstrated
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