Abstract
AbstractIn natural product discovery programs, the power of synthetic chemistry is often leveraged for the total synthesis and diversification of characterized metabolites. The synthesis of structures that are bioinformatically predicted to arise from uncharacterized biosynthetic gene clusters (BGCs) provides a means for synthetic chemistry to enter this process at an early stage. The recent identification of non-ribosomal peptides (NRPs) containing multiple ρ-aminobenzoic acids (PABAs) led us to search soil metagenomes for BGCs that polymerize PABA. Here, we use PABA-specific adenylation-domain sequences to guide the cloning of the lap BGC directly from soil. This BGC was predicted to encode a unique N-acylated PABA and thiazole containing structure. Chemical synthesis of this structure gave lapcin, a dual topoisomerase I/II inhibitor with nM to pM IC50s against diverse cancer cell lines. The discovery of lapcin highlights the power of coupling metagenomics, bioinformatics and total chemical synthesis to unlock the biosynthetic potential contained in even complex uncharacterized BGCs.
Funder
Foundation for the National Institutes of Health
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference45 articles.
1. Butler, M. S. Natural products to drugs: natural product derived compounds in clinical trials. Nat. Prod. Rep. 22, 162–195 (2005).
2. Koehn, F. E. & Carter, G. T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Disco. 4, 206–220 (2005).
3. Newman, D. J. & Cragg, G. M. Microbial antitumor drugs: Natural products of microbial origin as anticancer agents. Curr. Opin. Investigational Drugs 10, 1280–1296 (2009).
4. Wu, C. P., Ohnuma, S. & Ambudkar, S. V. Discovering natural product modulators to overcome multidrug resistance in cancer chemotherapy. Curr. Pharm. Biotechnol. 12, 609–620 (2011).
5. Chu, J. et al. Discovery of MRSA active antibiotics using primary sequence from the human microbiome. Nat. Chem. Biol. 12, 1004–1006 (2016).
Cited by
9 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献