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

• 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
• 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

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.

项目摘要 我们已经组建了一个完全以佛罗里达州为中心的合作研究团队， 天然产物化学和药理学，基因组学，细菌酶学，生物信息学，合成 生物学、化学合成、蓝细菌和海绵化学生态学和生物遗传学。该团队正在 并辅之以一位外州的宏基因组学和生物信息学整合专家。这一地理 在美国大陆拥有最大海洋生物多样性的州， 好处和独特的机会，探索系统，可能持有一些最有前途的方面， 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和独特的微生物组， 当地的生物多样性热点。已知由这些社区产生的化合物在治疗上覆盖 相关的化学空间，因此适合作为药物发现的起点。在有针对性的方式，我们 将获得高质量的（Meta）基因组和（Meta）转录组序列信息，从海绵相关 微生物组和蓝细菌使用国家的最先进的测序技术。我们将建立一个综合的，多- 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 工具，以发现新的生物合成基因簇的目标，特别是在他们的基因组闪耀新的光芒， 那些用现有的工具甚至化学骨架都无法达到的。我们将表达编码的天然产物 通过使用五种互补的合成生物学系统， 在过去的几年里发展起来的。这些系统起源于五个细菌门， 海洋蓝藻和海绵样本涵盖了不同的遗传背景，预计 有效地将各种生物的识别遗传信息转化为具有适当系统的化学品， 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NMR，并表征相关的新酶学。化学衍生的天然产物 提取物和级分文库以及通过我们的表达系统或化学合成产生的那些将被 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， 和体内模型以及实验和计算的基于靶点的功能测定。这种方法 将使我们能够从表达和未表达的基因中捕获广泛的活动。选择的生物活性 天然产物将通过化学合成进行规模化，并将制备生物探针和酶底物 分别用于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治疗重要的药物线索 和工具化合物，通过彻底探索海洋生物，同时解决目前的主要问题， 未来十年天然药物发现的局限性。