气候变化领域集成服务门户(CCPortal): Piperacillin triggers virulence factor biosynthesis via the oxidative stress response in Burkholderia thailandensis

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DOI	10.1073/pnas.2021483118
	Piperacillin triggers virulence factor biosynthesis via the oxidative stress response in Burkholderia thailandensis
	Li A.; Okada B.K.; Rosen P.C.; Seyedsayamdost M.R.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:26
英文摘要	Natural products have been an important source of therapeutic agents and chemical tools. The recent realization that many natural product biosynthetic genes are silent or sparingly expressed during standard laboratory growth has prompted efforts to investigate their regulation and develop methods to induce their expression. Because it is difficult to intuit signals that induce a given biosynthetic locus, we recently implemented a forward chemical-genetic approach to identify such inducers. In the current work, we applied this approach to nine silent biosynthetic loci in the model bacterium Burkholderia thailandensis to systematically screen for elicitors from a library of Food and Drug Administration–approved drugs. We find that β-lactams, fluoroquinolones, antifungals, and, surprisingly, calcimimetics, phenothiazine antipsychotics, and polyaromatic antidepressants are the most effective global inducers of biosynthetic genes. Investigations into the mechanism of stimulation of the silent virulence factor malleicyprol by the β-lactam piperacillin allowed us to elucidate the underlying regulatory circuits. Low-dose piperacillin causes oxidative stress, thereby inducing redox-sensing transcriptional regulators, which activate malR, a pathway-specific positive regulator of the malleicyprol gene cluster. Malleicyprol is thus part of the OxyR and SoxR regulons in B. thailandensis, allowing the bacterium to initiate virulence in response to oxidative stress. Our work catalogs a diverse array of elicitors and a previously unknown regulatory input for secondary metabolism in B. thailandensis. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Antibiotic; Biosynthesis; Burkholderia thailandensis; Natural product; Silent gene cluster
语种	英语
scopus关键词	antidepressant agent; antifungal agent; beta lactam antibiotic; malleicyprol; natural product; neuroleptic agent; phenothiazine; piperacillin; quinoline derived antiinfective agent; unclassified drug; virulence factor; beta lactam; piperacillin; reactive oxygen metabolite; virulence factor; Article; bacterial virulence; biosynthesis; Burkholderia thailandensis; controlled study; dose response; gene cluster; gene locus; high throughput elicitor screening; high throughput screening; nonhuman; oxidation reduction reaction; oxidative stress; regulon; secondary metabolism; silent gene; structure activity relation; transcription initiation; transcription regulation; antibiosis; biological model; Burkholderia; drug effect; gene expression regulation; genetic transcription; genetics; metabolism; physiology; Antibiosis; beta-Lactams; Biosynthetic Pathways; Burkholderia; Gene Expression Regulation, Bacterial; Models, Biological; Oxidation-Reduction; Oxidative Stress; Piperacillin; Reactive Oxygen Species; Secondary Metabolism; Transcription, Genetic; Virulence Factors
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/251143
作者单位	Department of Molecular Biology, Princeton University, Princeton, NJ 08544, United States; Department of Chemistry, Princeton University, Princeton, NJ 08544, United States
推荐引用方式 GB/T 7714	Li A.,Okada B.K.,Rosen P.C.,et al. Piperacillin triggers virulence factor biosynthesis via the oxidative stress response in Burkholderia thailandensis[J],2021,118(26).
APA	Li A.,Okada B.K.,Rosen P.C.,&Seyedsayamdost M.R..(2021).Piperacillin triggers virulence factor biosynthesis via the oxidative stress response in Burkholderia thailandensis.Proceedings of the National Academy of Sciences of the United States of America,118(26).
MLA	Li A.,et al."Piperacillin triggers virulence factor biosynthesis via the oxidative stress response in Burkholderia thailandensis".Proceedings of the National Academy of Sciences of the United States of America 118.26(2021).