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Exploring a New Dimension of Microbial Secondary Metabolism

探索微生物次生代谢的新维度

基本信息

批准号：
10623226
负责人：
Mohammad R Seyedsayamdost
金额：
$ 30.95万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-05 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623226
关键词：
Actinobacteria class Address Anabolism Antibiotics Bacteria Biochemistry Bioinformatics Biological Biology Burkholderia Cefotaxime Ceftazidime Cells Chemicals Chemistry Clinical Collection Coupled Detection Dimensions Dose Gene Cluster Genes Goals Growth Investigation Laboratories Learning Link Measures Metabolism Methodology Methods Microbial Physiology Myxococcales Natural Products Organism Pathway interactions Pharmacology Play Property Reactive Oxygen Species Regulation Regulatory Pathway Research Role Scheme Source Therapeutic Therapeutic Agents Time bacterial metabolism beta-Lactams biological adaptation to stress experimental study genome sequencing infancy innovation insight mass spectrometric imaging metabolome microbial model organism novel pharmacologic programs response screening secondary metabolite small molecule small molecule libraries transcriptome sequencing transcriptomics

项目摘要

ABSTRACT Bacterial natural products have provided an immense source of therapeutic agents and driven innovation in chemistry, biology, and pharmacology. In the past decade, it has become evident that the capacity of bacteria to synthesize natural products was vastly underestimated. Advances in genome and transcriptome sequencing combined with bioinformatic methods have shown that most biosynthetic genes are not expressed or, at best, sparingly expressed during standard laboratory growth; their products are therefore not synthesized at sufficient titers for detection and structural/functional characterization. These so-called ‘silent’ or ‘cryptic’ biosynthetic gene clusters outnumber constitutively active ones by a factor of 5-10. As such, they represent a new dimension of bacterial metabolism, and unlocking it will allow access to a wealth of new natural products and to deeper insights into microbial physiology and biochemistry. We recently contributed the High-Throughput Elicitor Screening (HiTES) methodology toward the discovery of cryptic metabolites. In this approach, small molecule libraries are screened to identify inducers of selected silent gene clusters. With elicitors identified, the cryptic metabolite and the regulation of the silent cluster can be investigated. Several aspects of HiTES remain unexplored and they form the basis for the current application: HiTES has only been applied to Burkholderia spp. and a few actinomycetes. Other prolific genera have not yet been targeted. Moreover, the mechanism underlying HiTES remains to be determined. Low-dose antibiotics have repeatedly been identified as the most effective elicitors, but the regulatory pathways that underpin this response remain to be elucidated. In the current application, we seek address these topics by expanding HiTES to prolific and understudied bacterial genera for the discovery of new, cryptic natural products with desired biological activities, and by elucidating the mechanisms with which low-dose antibiotics elicit cryptic metabolite biosynthesis, focusing on the β-lactam antibiotics and their stimulatory effect on the model organism Burkholderia thailandensis. Collectively, these studies will shed light on an emerging dimension of bacterial secondary metabolism, unearth new regulatory circuits that drive expression of silent gene clusters, and provide novel natural products as possible therapeutic leads and sources of biosynthetic and pharmacological investigations.

摘要

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Small-Molecule Language of Dynamic Microbial Interactions.

动态微生物相互作用的小分子语言。

DOI：
10.1146/annurev-micro-042722-091052
发表时间：
2022
期刊：
Annual review of microbiology
影响因子：
10.5
作者：
Zhang,Yifan;Gallant,Étienne;Park,Jong-Duk;Seyedsayamdost,MohammadR
通讯作者：
Seyedsayamdost,MohammadR

Structural Elucidation of Cryptic Algaecides in Marine Algal-Bacterial Symbioses by NMR Spectroscopy and MicroED.

DOI：
10.1002/anie.202114022
发表时间：
2022-01-21
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
影响因子：
16.6
作者：
Park, Jong-Duk;Li, Yuchen;Moon, Kyuho;Han, Esther J.;Lee, Seoung Rak;Seyedsayamdost, Mohammad R.
通讯作者：
Seyedsayamdost, Mohammad R.

Induction of Diverse Cryptic Fungal Metabolites by Steroids and Channel Blockers.