Experiment based genome mining of ribosomal natural products

基于实验的核糖体天然产物基因组挖掘

• 批准号: 8838182
• 负责人: PIETER C DORRESTEIN
• 金额: $ 46.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838182
• 关键词: Algorithms; Amino Acids; Bacillus cereus; Biochemistry; Biological Factors; Biology; Chemistry; Cholesterol; Chronic Disease; Clostridium difficile; Coculture Techniques; Data; Defensins; Detection; Development; Eukaryota; Future; Genetic; Genetic Identity; Genome; Genomics; Harvest; Human; Image; In Vitro; Infection; Invertebrates; Lasso; Lead; Malignant Neoplasms; Marines; Mass Spectrum Analysis; Metabolic Diseases; Methodology; Microbe; Mining; Multi-Drug Resistance; Nature; Organism; Penicillins; Peptides; Pharmaceutical Preparations; Post-Translational Protein Processing; Prevalence; Primates; Property; Proteomics; Published Comment; RNA; Snails; Source; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staging; Staphylococcus aureus; Structure; Structure-Activity Relationship; Techniques; Therapeutic; Toxin; Translations; Viral; Work; analog; antimicrobial drug; bacteriocin; base; falls; genome sequencing; interest; metabolomics; microbial; microcin; novel; novel therapeutics; pathogenic bacteria; programs; reconstitution; research study; response; screening; tandem mass spectrometry; therapeutic development; tool

DESCRIPTION (provided by applicant): Ribosomally encoded natural products were once thought to be of limited structural diversity and uncommon amongst microbes. Over the past few years, however, this viewpoint has changed due to the increased discovery rate of RNPs possessing newly described structural motifs previously ascribed to their nonribosomal counterparts. Nearly every sequenced genome, including invertebrates, contains the genetic capacity to biosynthesize ribosomally- encoded, post-translationally modified natural products such as lantibiotics, bacteriocins, microcins, cyanobactins, thiopeptides, and lasso peptides, thereby making this class of underappreciated natural products perhaps the most dominant in all of nature. What is lacking, however, is a systematic approach to harvest this ubiquitous class of natural products and assess their unique biosynthetic capacity. The difficulty associated with characterizing RNPs in a systematic fashion can be attributed to their falling outside the scope of not only most therapeutic screening programs but also metabolomic or proteomic approaches due to their larger size, structural diversity and extraordinary number of post-translational modifications. This proposal outlines the developmental strategies to create a set of tools for harnessing the biosynthetic potential of ribosomally encoded natural products through mass spectrometry based genome mining. The techniques and methodologies created as a result of the proposed work will not only be important for the detection of therapeutic lead compounds, but also for the efficient characterization of ribosomally encoded toxins secreted by pathogenic bacteria such as Staphylococcus aureus, Bacillus cereus and Clostridium difficile as well as defensins produced by higher eukaryotes such as marine snails, primates and humans.

描述（由申请人提供）：核糖体编码的天然产物曾经被认为具有有限的结构多样性，并且在微生物中罕见。然而，在过去的几年中，由于具有新描述的结构基序的RNP的发现率提高，因此这种观点发生了变化。几乎每个测序的基因组，包括无脊椎动物，都包含生物合成的遗传能力，以核糖体编码，翻译后修饰的天然产物，例如盐位生物，细菌蛋白，微蛋白，氰基甲酰胺，硫代蛋白，硫代肽和诸如较少的天然产物的分类，既可以构成自然的产品，又可以构成这种类别的自然产品。然而，缺少的是一种系统的方法，可以收获这种无处不在的天然产品，并评估其独特的生物合成能力。与以系统的方式表征RNP相关的困难可能归因于它们不仅超出了大多数治疗性筛查程序的范围，而且由于其较大的尺寸，结构多样性和特殊数量的翻译后修饰而属于代谢组或蛋白质组学方法。 该提议概述了创建一组工具来利用核糖体编码天然产物的生物合成潜力的工具的发展策略，该策略通过基于质谱的基因组挖掘的生物合成潜力。由于提出的工作而创建的技术和方法不仅对检测治疗性铅化合物的检测至关重人类。

项目成果

Pep2Path: automated mass spectrometry-guided genome mining of peptidic natural products.

• DOI: 10.1371/journal.pcbi.1003822
• 发表时间: 2014-09
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Medema MH;Paalvast Y;Nguyen DD;Melnik A;Dorrestein PC;Takano E;Breitling R
• 通讯作者: Breitling R

Vitroprocines, new antibiotics against Acinetobacter baumannii, discovered from marine Vibrio sp. QWI-06 using mass-spectrometry-based metabolomics approach.

Vitroprocines 是一种针对鲍曼不动杆菌的新型抗生素，从海洋弧菌中发现。

• DOI: 10.1038/srep12856
• 发表时间: 2015
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Liaw,Chih-Chuang;Chen,Pei-Chin;Shih,Chao-Jen;Tseng,Sung-Pin;Lai,Ying-Mi;Hsu,Chi-Hsin;Dorrestein,PieterC;Yang,Yu-Liang
• 通讯作者: Yang,Yu-Liang

Biosynthetic multitasking facilitates thalassospiramide structural diversity in marine bacteria.

• DOI: 10.1021/ja3119674
• 发表时间: 2013-01-23
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Ross, Avena C.;Xu, Ying;Lu, Liang;Kersten, Roland D.;Shao, Zongze;Al-Suwailem, Abdulaziz M.;Dorrestein, Pieter C.;Qian, Pei-Yuan;Moore, Bradley S.
• 通讯作者: Moore, Bradley S.