Engineered production and evaluation of 6′-deoxy-tallysomycin H-1 revealing new insights into the structure–activity relationship of the anticancer drug bleomycin

The bleomycins (BLMs), a family of glycopeptide antibiotics, are currently used clinically in combination with a number of other agents for the treatment of malignant tumors. Other members of the BLM family include tallysomycins (TLMs), phleomycins and zorbamycin (ZBM). We previously cloned and char...

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Bibliographic Details
Published in:Journal of antibiotics 2018-01, Vol.71 (1), p.97-103
Main Authors: Yang, Dong, Hindra, Dong, Liao-Bin, Crnovcic, Ivana, Shen, Ben
Format: Article
Language:English
Subjects:
38/44
631/326/325
639/638/60
Antibiotics
Anticancer properties
Antineoplastic drugs
Antitumor activity
Antitumor agents
Bacteriology
Biomedical and Life Sciences
Bioorganic Chemistry
Biosynthesis
Bleomycin
Cancer
Cleavage
Combinatorial analysis
Deoxyribonucleic acid
Disaccharides
DNA
Evaluation
Gene clusters
Gene expression
Glycopeptides
Life Sciences
Medicinal Chemistry
Metabolites
Microbiology
Organic Chemistry
original-article
Tallysomycin
Tumors
Zorbamycin
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Summary:The bleomycins (BLMs), a family of glycopeptide antibiotics, are currently used clinically in combination with a number of other agents for the treatment of malignant tumors. Other members of the BLM family include tallysomycins (TLMs), phleomycins and zorbamycin (ZBM). We previously cloned and characterized the biosynthetic gene clusters for BLMs, TLMs and ZBM. Applications of combinatorial biosynthesis strategies to the three biosynthetic machineries enabled the engineered production of several BLM analogs with unique structural characteristics and varying DNA cleavage activities, thereby providing an outstanding opportunity to study the structure–activity relationship (SAR) for the BLM family of anticancer drugs. We now report the engineered production of a new BLM–TLM–ZBM hybrid metabolite, named 6′-deoxy-TLM H-1, which consists of the 22-desmethyl-BLM aglycone, the TLM A C-terminal amine and the ZBM disaccharide, by heterologous expression of the zbmGL genes from the ZBM biosynthetic gene cluster in the Streptoalloteichus hindustanus Δ tlmH mutant strain SB8005. Evaluation of the DNA cleavage activities of 6′-deoxy-TLM H-1 as a measurement for its potential anticancer activity, in comparison with TLM H-1 and BLM A2, reveals new insight into the SAR of BLM family of anticancer drugs.
ISSN:0021-8820
1881-1469
DOI:10.1038/ja.2017.93