Discovery of Antibiotics from Soil Microbiomes Using Metagenomics

利用宏基因组学从土壤微生物组中发现抗生素

• 批准号: 10552394
• 负责人: SEAN F BRADY
• 金额: $ 59.33万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552394
• 关键词: Antibiotics; Bacteria; Base Sequence; Bioinformatics; Cloning; Culture-independent methods; DNA; Development; Disease; Drug Screening; Environment; Gene Cluster; Genomics; Goals; Industrialization; Laboratories; Lead; Left; Medical; Metagenomics; Methods; Multi-Drug Resistance; Natural History; Natural Products; Nature; Productivity; Recording of previous events; Research; Sampling; Soil; Source; Structure; Surface; Work; bioactive natural products; clinically relevant; design; metagenome; method development; microbiome; multi-drug resistant pathogen; novel; novel therapeutics; pathogen; programs; screening; small molecule; success

Project Summary: Bacterial natural products have a long history of serving as lead structures for the development of new therapeutically relevant small molecules. Despite the tremendous early success of bacterial natural product discovery programs, both academic and industrial drug screening efforts have largely deprioritized natural products in recent years due to unacceptably high rediscovery rates, which were often taken as an indication that nature had few novel small molecules left for us to identify. Extensive sequencing of both bacterial genomic and metagenomic DNA indicates that this is, in fact, not the case. Instead, it appears that we have just begun to scratch the surface of the structural and functional diversity of small molecules encoded by the global microbiome. In most environments uncultured bacteria still significantly outnumber their cultured counterparts, and even when it is possible to grow bacteria in the laboratory they usually only express a small subset of their natural product biosynthetic gene clusters. My research group is focused on the development of culture-independent (metagenomic) approaches for identifying novel natural products encoded provides a means of accessing this large fraction of previously inaccessible biosynthetic diversity. In these studies, the need to culture bacteria is circumvented by extracting DNA directly from environmental samples and cloning it into easily cultured bacteria. This proposal is designed to continue our development of culture-independent methods for accessing the natural products encoded in soil metagenomes and to increasingly apply these methods to the discovery and characterization of new bioactive small molecules. In particular, our studies will include the development of new sequence-based and functional metagenomic screening methods as well as the use of heterologous expression and synthetic bioinformatic natural product discovery approaches to generate novel small molecules from soil metagenome derived biosynthetic gene clusters. Method develop studies will be focus on overcoming key technical hurdles to enable the more efficient and higher throughput discovery of structurally and mechanistically different natural products from metagenomes using both bioinformatic and unbiased functional screening approaches. As with traditional natural product discovery programs, our ultimate goal is to identify bioactive small molecules that have the potential to be used as lead structures for the development of novel therapeutics. Although our metagenomic methods can be applied to the identification of compounds that can target almost any disease, we will primarily focus on the discovery of new antibiotics. This choice is driven by the long history of natural products being the most productive source of potent antibiotics with unique modes of actions and the clear biomedical need for new antibiotics that are effective against clinically relevant, multi-drug resistant, Gram-positive and Gram-negative pathogens.

项目概要： 细菌天然产物作为开发新的微生物的先导结构具有悠久的历史。 治疗相关的小分子。尽管细菌天然产物在早期取得了巨大的成功， 发现计划，学术和工业药物筛选工作都在很大程度上降低了天然药物的优先级。 近年来，由于再发现率高得令人无法接受， 自然界中几乎没有新的小分子留给我们去识别。两种细菌的广泛测序 基因组和宏基因组DNA表明，事实并非如此。相反，我们似乎 我们才刚刚开始触及小分子的结构和功能多样性的表面，这些小分子是由 全球微生物组在大多数环境中，未培养的细菌数量仍然大大超过其培养的细菌数量。 即使在实验室中可以培养细菌，它们通常也只表达一小部分。 其天然产物生物合成基因簇的子集。我的研究小组专注于 用于鉴定编码的新型天然产物的不依赖培养物的（宏基因组）方法提供了一种 这是一种获取以前无法获取的生物合成多样性的手段。在这些研究中， 通过直接从环境样本中提取DNA并克隆它， 转化成易于培养的细菌这一建议旨在继续我们的文化独立发展， 获取土壤宏基因组中编码的天然产物的方法，并越来越多地应用这些方法， 新的生物活性小分子的发现和表征的方法。特别是，我们的研究将 包括开发新的基于序列和功能的宏基因组筛选方法，以及 异源表达和合成生物信息学天然产物发现方法的使用， 从土壤宏基因组衍生的生物合成基因簇中产生新的小分子。方法开发 研究将集中在克服关键技术障碍，以实现更有效和更高的吞吐量。 使用这两种方法从宏基因组发现结构和机制不同的天然产物 生物信息学和无偏见的功能筛选方法。与传统的天然产品发现一样， 项目，我们的最终目标是确定有可能被用作铅的生物活性小分子 用于开发新疗法的结构。虽然我们的宏基因组方法可以应用于 鉴定几乎可以靶向任何疾病的化合物，我们将主要集中在发现 新的抗生素这种选择是由天然产品作为最具生产力的来源的悠久历史所驱动的 具有独特作用模式的强效抗生素，以及对新抗生素的明确生物医学需求， 有效对抗临床相关的、多重耐药的、革兰氏阳性和革兰氏阴性病原体。

项目成果

Refactoring biosynthetic gene clusters for heterologous production of microbial natural products.

• DOI: 10.1016/j.copbio.2020.12.011
• 发表时间: 2021-06
• 期刊: Current opinion in biotechnology
• 影响因子: 7.7
• 作者: Li L;Maclntyre LW;Brady SF
• 通讯作者: Brady SF

A Family of Antibiotics That Evades Resistance by Binding Polyprenyl Phosphates.

通过结合聚异戊二烯磷酸酯来逃避耐药性的抗生素家族。

• DOI: 10.1021/acsinfecdis.3c00475
• 发表时间: 2023
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Rosenzweig,AdamF;Wang,Zongqiang;Morales-Amador,Adrián;Spotton,Kaylyn;Brady,SeanF
• 通讯作者: Brady,SeanF

Commensal bacteria make GPCR ligands that mimic human signalling molecules.

共生细菌使GPCR配体模仿人类信号分子。

• DOI: 10.1038/nature23874
• 发表时间: 2017-09-07
• 期刊: Nature
• 影响因子: 64.8
• 作者: Cohen LJ;Esterhazy D;Kim SH;Lemetre C;Aguilar RR;Gordon EA;Pickard AJ;Cross JR;Emiliano AB;Han SM;Chu J;Vila-Farres X;Kaplitt J;Rogoz A;Calle PY;Hunter C;Bitok JK;Brady SF
• 通讯作者: Brady SF

A naturally inspired antibiotic to target multidrug-resistant pathogens.

• DOI: 10.1038/s41586-021-04264-x
• 发表时间: 2022-01
• 期刊: Nature
• 影响因子: 64.8

Bacterial natural product biosynthetic domain composition in soil correlates with changes in latitude on a continent-wide scale.

• DOI: 10.1073/pnas.1710262114
• 发表时间: 2017-10-31
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Lemetre, Christophe;Maniko, Jeffrey;Brady, Sean F
• 通讯作者: Brady, Sean F