Multi-Omics And Synbio Enabled Discovery Of Antifungal Fernene Triterpenes

多组学和 Synbio 发现抗真菌蕨烯三萜

• 批准号: 10601431
• 负责人: NEIL L KELLEHER
• 金额: $ 30万
• 依托单位: VARIGEN BIOSCIENCES CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601431
• 关键词: 3-Dimensional; Affect; Anabolism; Antifungal Agents; Aspergillus fumigatus; Aspergillus nidulans; Bioinformatics; Biological Assay; Biology; Candida; Candida albicans; Candida auris; Chemicals; Chemistry; Clinical; Cloning; Cyclization; Data; Development; Distant; Engineering; Enzymes; Family; Gene Cluster; Generations; Genes; Genome; Genomics; Genotype; Glucose; Goals; Healthcare Systems; Infection; Lead; Length; Life; Link; Marketing; Mass Spectrum Analysis; Measures; Metabolic; Methods; Mining; Multi-Drug Resistance; Mycoses; Natural Products; Oral; Organism; Outcome; Pathway interactions; Patients; Phenotype; Proteins; Recording of previous events; Reporting; Research; Resources; Rest; Shuttle Vectors; Signal Transduction; Structure; Structure-Activity Relationship; Technology; Terpenes; Therapeutic; Time; Transferase; Triterpenes; Universities; Variant; Vertebral column; Wisconsin; Work; analog; design; fungus; genome analysis; glucan synthase; glycosyltransferase; human pathogen; inhibitor; insight; interest; metabolic profile; metabolomics; multiple omics; novel; novel therapeutics; pathogenic fungus; programs; promoter; scaffold; secondary metabolite; sequencing platform; synthetic biology; tool; whole genome

Project Summary. A new functional metabologenomics approach is proposed for the development of a second generation of fernene-based antifungal terpenes. Our team led by Mead (Varigen), Keller (University of Wisconsin) and Kelleher (Northwestern University) explore the diversity of this unique family of triterpenes using a fusion of technologies that unites genomics with metabolomic understanding of fungal terpene synthesis. We begin by applying a genome mining-driven approach to find new natural analogs of enfumafungin. The resulting data are then integrated with metabolomic analysis and antifungal bioactivity assay data to establish the putative enfumafungin-like metabolites encoded by diverse strains and ultimately chart the structure-activity relationship space within this potent class of antifungals. In parallel, our team is constructing a modular platform capable of generating hundreds of different analogs in functional amounts. Here, we will heterologously express the enfumafungin-like pathways from fungal strains in an engineered Aspergillus nidulans host. The sequence- specific cloning and heterologous expression of lead molecules discovered in this program will establish methods to conduct targeted swapping of cyclase genes across multiple species to generate new antifungal fernene-like scaffolds. The long-term goal, requiring additional resources, is to advance a second generation of triterpene antifungal analogs into the research and clinical market place. Overall, this program provides an important next step towards establishing functional metabologenomics as a viable tool to go from genome to functional therapeutic. As a testbed, we turn to a natural product family with a recent history of clinical utility for the development of new analogs and technologies to access them.

项目摘要。提出了一种新的功能化元素学方法，以开发第二秒 基于fernene的抗真菌萜烯的产生。我们的团队由Mead（Varigen），Keller（University of Mead）领导 威斯康星州）和凯勒尔（西北大学）探索了这种独特的三萜家族的多样性 将基因组学与对真菌萜烯合成的代谢组理解融合的技术融合。我们 首先采用基因组开采驱动的方法来找到新的enfumafungin的天然类似物。结果 然后将数据与代谢组学分析和抗真菌生物活性测定数据集成在一起，以建立推定的 由多种菌株编码的Enfumafungin样代谢产物，最终绘制了结构活性关系 在这一有效的抗真菌类别中的空间。同时，我们的团队正在构建一个模块化平台 产生数百种不同类似物的功能量。在这里，我们将异源表达 工程化曲霉的Nidulans宿主中的真菌菌株的Enfumafungin样途径。序列 - 在该程序中发现的铅分子的特定克隆和异源表达将建立方法 进行针对性交换跨多种物种的循环酶基因，以产生新的抗真菌狂热样 脚手架。需要额外资源的长期目标是促进第二代三萜 抗真菌类似物进入研究和临床市场。总体而言，该计划提供了重要的下一个 迈向建立功能性替代元素学作为从基因组到功能的可行工具 治疗性。作为测试台，我们转向具有最近临床实用程序历史的天然产品家族 开发新的类似物和技术来访问它们。