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.

抽象的细菌天然产品提供了巨大的热代理和驱动创新的来源化学，生物学和药理学。在过去的十年中，它已成为证据表明合成天然产物的细菌被大大低估。基因组和转录组的进步结合生物信息学方法的测序表明，大多数生物合成基因不是在标准实验室增长期间表达或充其量是很少表达的；因此，他们的产品不是在足够的滴度上合成用于检测和结构/功能表征。这些所谓的“沉默” 或“神秘的”生物合成基因的组成性活性为5-10。因此，他们代表细菌代谢的新维度，解锁将允许获得大量新的天然产品以及对微生物生理和生物化学的更深入了解。我们最近为高通量引发筛选（HITE）方法贡献了发现加密代谢物。在这种方法中，筛选小分子库以识别诱导剂选定的无声基因簇。通过确定引发者，加密代谢物和沉默的调节可以研究群集。 HITE的几个方面仍然出乎意料，它们构成了当前申请：HITE仅应用于Burkholderia spp。还有一些放线菌。其他多产属尚未成为目标。此外，命中率的机制仍有待确定。低剂量抗生素反复被确定为最有效的引起剂，但是调节支撑此反应的途径尚待阐明。在当前申请中，我们寻求地址这些主题通过将杀伤力扩展到多产并理解细菌属，以发现新的加密货币具有所需生物活性的天然产品，并通过阐明低剂量的机制抗生素会引起加密代谢物生物合成，重点是β-内酰胺抗生素及其刺激性对模型生物Burkholderia Thailandensis的影响。这些研究共同阐明了细菌次生代谢的新兴维度，发掘的新调节电路，以驱动表达沉默的基因簇，并提供新颖的天然产物作为可能的治疗铅和来源生物合成和药物研究。

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.