Integrative Multidisciplinary Discovery Platform to Unlock Marine Natural Products Therapeutic Opportunities

综合多学科发现平台释放海洋天然产品治疗机会

基本信息

批准号：
10669734
负责人：
Mohamed Abou Donia
金额：
$ 176.06万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669734
关键词：
Actinobacteria class Action Research Address Anabolism Antibody-drug conjugates Artificial Intelligence Bacteroidetes Biochemistry Biodiversity Bioinformatics Biological Biological Assay Bioprobe Breathing CRISPR/Cas technology Caenorhabditis elegans Cell physiology Chemicals Collaborations Collection Communities Complement Coupled Crude Extracts Cyanobacterium Cytology Development Developmental Process Dimensions Disease Dolastatin 10 Drug Targeting Ecology Enzymatic Biochemistry Enzymes FDA approved Family Firmicutes Florida Future G-Protein-Coupled Receptors Gene Cluster Gene Expression Profiling Generations Genes Genetic Genome Genomics Geography Goals Grant In Vitro Interdisciplinary Study Joints Knowledge Libraries Light Link Mammalian Cell Metagenomics Methodology Microbe Mining Molecular Natural Product Drug Natural Products Natural Products Chemistry Natural Resources Natural Selections Nature Organic Chemistry Organism Pathway interactions Pharmaceutical Preparations Pharmacology Phenotype Phylogenetic Analysis Physiological Processes Porifera Proteins Proteobacteria Publications RNA Interference Research Research Personnel Sampling Skeleton Structure System Systems Biology Techniques Testing Therapeutic Therapeutic Uses Translating United States National Institutes of Health Yeasts apratoxin bioactive natural products bioinformatics tool cellular targeting chemical synthesis computational chemistry coral deletion library drug candidate drug development drug discovery enzyme substrate fitness genetic information genome analysis genome sequencing in vivo in vivo Model innovation interdisciplinary approach marine marine natural product marine organism member metabolomics metagenome microbial microbiome microorganism multidisciplinary novel novel therapeutics scaffold screening structural biology success synthetic biology tool transcriptome transcriptomics

项目摘要

PROJECT SUMMARY We have assembled an entirely Florida-centric collaborative research team with collective expertise in microbial natural products chemistry and pharmacology, genomics, bacterial enzymology, bioinformatics, synthetic biology, chemical synthesis, and cyanobacterial and sponge chemical ecology and phylogenetics. The team is complemented by an out-of-state expert in metagenomics and bioinformatics integration. This geographical cluster of expertise being in the state with the greatest marine biodiversity in the continental US provides a dual benefit and unique opportunity to explore systems that are likely to hold some of the most promise in terms of biosynthetic potential: marine cyanobacterial communities, consisting of benthic filamentous cyanobacteria that are associated with unique microbial diversity, and sponges and their associated rich and unique microbiome in a local hotspot of biodiversity. Compounds produced by these communities are known to cover therapeutically relevant chemical space and are therefore suited as starting points for drug discovery. In a targeted fashion, we will obtain high quality (meta)genome and (meta)transcriptome sequence information from sponge-associated microbiomes and cyanobacteria using state-of-the-art sequencing techniques. We will build an integrated, multi- component platform that leverages existing bioinformatics tools and newly developed artificial intelligence-based tools to shine new light at their genomes with the goal of identifying novel biosynthetic gene clusters, particularly those unattainable with current tools, and even chemical skeletons. We will express natural products encoded by the clusters by employing five types of complementary synthetic biology systems that we have strategically developed over the past several years. These systems originating from five bacterial phyla commonly associated with both marine cyanobacterial and sponge samples cover diverse genetic backgrounds and are expected to effectively translate the identified genetic information of a variety of organisms into chemicals with proper system optimization. We will evaluate and analyze metabolites and expression profiles using LC-MS-based metabolomics and NMR and characterize associated new enzymology. Natural products derived from chemical extract and fraction libraries and those generated through our expression systems or chemical synthesis will be tested in our multidimensional screening platform, consisting of unbiased phenotypic assays in various in vitro and in vivo models as well as experimental and computational target-based functional assays. This approach will enable us to capture a broad array of activities from expressed and unexpressed genes. Selected bioactive natural products will be scaled by chemical synthesis, and bioprobes and enzyme substrates will be prepared for in-depth biological studies and enzymology research, respectively. Successful completion of these aims by our established multidisciplinary investigator team should deliver promising therapeutically important drug leads and tool compounds through thoroughly exploring marine organisms while addressing the current major limitations of natural products drug discovery over the next ten years.

项目概要我们组建了一个完全以佛罗里达州为中心的合作研究团队，拥有微生物方面的集体专业知识天然产物化学与药理学、基因组学、细菌酶学、生物信息学、合成生物学、化学合成、蓝藻和海绵化学生态学和系统发育学。该团队是由宏基因组学和生物信息学整合方面的州外专家进行补充。这个地理位于美国大陆海洋生物多样性最丰富的州的专业知识集群提供了双重优势好处和独特的机会来探索可能在以下方面最有希望的系统生物合成潜力：海洋蓝藻群落，由底栖丝状蓝藻组成，与独特的微生物多样性有关，海绵及其相关的丰富而独特的微生物组当地生物多样性热点地区。已知这些群落产生的化合物具有治疗作用相关的化学空间，因此适合作为药物发现的起点。我们以有针对性的方式将从海绵相关的高质量（元）基因组和（元）转录组序列信息使用最先进的测序技术对微生物组和蓝藻进行研究。我们将建设一个综合性、多元化的利用现有生物信息学工具和新开发的基于人工智能的组件平台为基因组带来新光的工具，目的是识别新的生物合成基因簇，特别是现有工具甚至化学骨架无法实现的目标。我们将编码表达天然产物通过采用我们战略性拥有的五种互补合成生物学系统来进行集群经过过去几年的发展。这些系统起源于通常相关的五个细菌门海洋蓝藻和海绵样本涵盖不同的遗传背景，预计通过适当的系统有效地将已识别的多种生物体的遗传信息转化为化学物质优化。我们将使用基于 LC-MS 的方法评估和分析代谢物和表达谱代谢组学和核磁共振并表征相关的新酶学。化学衍生的天然产品提取物和级分文库以及通过我们的表达系统或化学合成生成的文库将在我们的多维筛选平台中进行了测试，包括各种体外无偏表型测定和体内模型以及基于实验和计算目标的功能测定。这种做法将使我们能够捕获表达和未表达基因的广泛活动。精选生物活性天然产物将通过化学合成进行规模化，并制备生物探针和酶底物分别进行深入的生物学研究和酶学研究。成功完成这些目标我们建立的多学科研究团队应该提供有希望的、具有重要治疗意义的药物先导化合物和工具化合物，通过彻底探索海洋生物，同时解决当前的主要问题未来十年天然产物药物发现的局限性。