气候变化领域集成服务门户(CCPortal): A comparative metabologenomic approach reveals mechanistic insights into Streptomyces antibiotic crypticity

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DOI	10.1073/pnas.2103515118
	A comparative metabologenomic approach reveals mechanistic insights into Streptomyces antibiotic crypticity
	Qi Y.; Nepal K.K.; Blodgett J.A.V.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:31
英文摘要	Streptomyces genomes harbor numerous, biosynthetic gene clusters (BGCs) encoding for drug-like compounds. While some of these BGCs readily yield expected products, many do not. Biosynthetic crypticity represents a significant hurdle to drug discovery, and the biological mechanisms that underpin it remain poorly understood. Polycyclic tetramate macrolactam (PTM) antibiotic production is widespread within the Streptomyces genus, and examples of active and cryptic PTM BGCs are known. To reveal further insights into the causes of biosynthetic crypticity, we employed a PTM-targeted comparative metabologenomics approach to analyze a panel of S. griseus clade strains that included both poor and robust PTM producers. By comparing the genomes and PTM production profiles of these strains, we systematically mapped the PTM promoter architecture within the group, revealed that these promoters are directly activated via the global regulator AdpA, and discovered that small promoter insertion–deletion lesions (indels) differentiate weaker PTM producers from stronger ones. We also revealed an unexpected link between robust PTM expression and griseorhodin pigment coproduction, with weaker S. griseus–clade PTM producers being unable to produce the latter compound. This study highlights promoter indels and biosynthetic interactions as important, genetically encoded factors that impact BGC outputs, providing mechanistic insights that will undoubtedly extend to other Streptomyces BGCs. We highlight comparative metabologenomics as a powerful approach to expose genomic features that differentiate strong, antibiotic producers from weaker ones. This should prove useful for rational discovery efforts and is orthogonal to current engineering and molecular signaling approaches now standard in the field. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cryptic metabolism; Metabologenomics; Regulation; Streptomyces griseus; Tetramic acid
语种	英语
scopus关键词	antiinfective agent; bacterial genome; gene deletion; gene expression regulation; genetics; genomics; metabolism; physiology; promoter region; Streptomyces; Anti-Bacterial Agents; Gene Deletion; Gene Expression Regulation, Bacterial; Genome, Bacterial; Genomics; Promoter Regions, Genetic; Streptomyces
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251094
作者单位	Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States
推荐引用方式 GB/T 7714	Qi Y.,Nepal K.K.,Blodgett J.A.V.. A comparative metabologenomic approach reveals mechanistic insights into Streptomyces antibiotic crypticity[J],2021,118(31).
APA	Qi Y.,Nepal K.K.,&Blodgett J.A.V..(2021).A comparative metabologenomic approach reveals mechanistic insights into Streptomyces antibiotic crypticity.Proceedings of the National Academy of Sciences of the United States of America,118(31).
MLA	Qi Y.,et al."A comparative metabologenomic approach reveals mechanistic insights into Streptomyces antibiotic crypticity".Proceedings of the National Academy of Sciences of the United States of America 118.31(2021).