This study successfully produced gilvusmycin by harnessing two highly homologous BGCs of gilvusmycin and CC-1065.Although no BGC has been identified for this natural product so far, our work strongly suggests that this BGC from Streptomyces indeed encodes gilvusmycin.We have successfully produced gilvusmycin by harnessing two highly homologous BGCs of gilvusmycin and CC-1065.Although no BGC has been identified for this natural product so far, our work strongly suggests that this BGC from Streptomyces sp.NRRL B-1347 (and S. yokosukanensis DSM 40224) indeed encodes gilvusmycin.Related BGCs are also natural DNA elements that can be used for synthetic biol.For example, compound 3 here is a newly discovered 'unnatural' natural product.Therefore, the strategy used in our present study is significant because such a strategy can also be harnessed to create new mols. using highly homologous BGCs.

01 Jan 1999·The Journal of AntibioticsQ4 · MEDICINE

Gilvusmycin, a New Antitumor Antibiotic Related to CC-1065.

Q4 · MEDICINE

Article

Author: Toshiyuki Isoe ; Yusuke Tokoro ; Kazutoshi Shindo

A new antitumor antibiotic gilvusmycin was isolated from the culture broth of Streptomyces sp. QM16. The structure of gilvusmycin was related to CC-1065 and determined by NMR spectral analysis. Gilvusmycin exhibited antitumor activity against murine leukemia P388 in vivo.

Nature CommunicationsQ1 · CROSS-FIELD

Structural evolution of a DNA repair self-resistance mechanism targeting genotoxic secondary metabolites

Q1 · CROSS-FIELD

ArticleOA

Author: Dorival, Jonathan ; Eichman, Brandt F ; Mullins, Elwood A ; Tang, Gong-Li ; Boger, Dale L

AbstractMicrobes produce a broad spectrum of antibiotic natural products, including many DNA-damaging genotoxins. Among the most potent of these are DNA alkylating agents in the spirocyclopropylcyclohexadienone (SCPCHD) family, which includes the duocarmycins, CC-1065, gilvusmycin, and yatakemycin. The yatakemycin biosynthesis cluster inStreptomycessp. TP-A0356 contains an AlkD-related DNA glycosylase, YtkR2, that serves as a self-resistance mechanism against yatakemycin toxicity. We previously reported that AlkD, which is not present in an SCPCHD producer, provides only limited resistance against yatakemycin. We now show that YtkR2 and C10R5, a previously uncharacterized homolog found in the CC-1065 biosynthetic gene cluster ofStreptomyces zelensis, confer far greater resistance against their respective SCPCHD natural products. We identify a structural basis for substrate specificity across gene clusters and show a correlation between in vivo resistance and in vitro enzymatic activity indicating that reduced product affinity—not enhanced substrate recognition—is the evolutionary outcome of selective pressure to provide self-resistance against yatakemycin and CC-1065.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	JP	Kirin Brewery Co. Ltd.	-

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