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Multi-Omics And Synbio Enabled Discovery Of Antifungal Fernene Triterpenes

多组学和 Synbio 发现抗真菌蕨烯三萜

基本信息

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
项目类别：
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

项目摘要

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.

项目总结。提出了一种新的功能代谢基因组学方法来开发第二种