A Platform to Identify Antifungal Compounds with Novel Action Mechanisms

鉴定具有新颖作用机制的抗真菌化合物的平台

• 批准号: 10760421
• 负责人: Chengcang Charles Wu
• 金额: $ 30.02万
• 依托单位: INTACT GENOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10760421
• 关键词: Academia; American; Anti-Infective Agents; Antifungal Agents; Antifungal Therapy; Artificial Chromosomes; Ascomycota; Aspergillus nidulans; Bioinformatics; Businesses; Cancer Patient; Cells; Chemical Structure; Chemicals; Chemistry; Cloning; Collaborations; Collection; Communicable Diseases; Development; Drug Interactions; Epidemic; Erythrocytes; Excretory function; Fungal Drug Resistance; Fungal Genome; Gene Cluster; Genome; Genomics; Goals; Grant; Human; Immunocompromised Host; India; Individual; Intensive Care Units; Length; Libraries; Licensing; Life; Medical; Metabolism; Metagenomics; Methodology; Methods; Molds; Molecular Target; Mucormycosis; Mycoses; Natural Compound; Natural Products; Pharmaceutical Preparations; Phase; Phenotype; Probability; Property; Public Health; Publications; RNA; Research; Research Proposals; Resistance; Resources; Rhizopus; Science; Scientist; Services; Side; Small Business Innovation Research Grant; Source; Structure; System; Technology; Therapeutic; Therapeutic immunosuppression; Toxic effect; Triage; United States National Institutes of Health; Universities; Wisconsin; Work; absorption; candidate identification; chemotherapy; clinical development; combat; cost; cytotoxicity; deep sequencing; drug discovery; fighting; forgetting; fungicide; fungus; improved; in vivo; interest; lead candidate; microbial; neglect; new technology; novel; pandemic disease; pathogenic fungus; pre-clinical; screening; secondary infection; side effect; small molecule; success; tool; transcriptome sequencing; treatment strategy

Project Summary There is societal need for new compounds in our arsenal of defenses against fungal pathogens, many of which are increasingly resistant to existing therapeutics. Antifungal compound discovery has been forgotten or neglected (see a review publication 2021 at Research Strategy). One of the best possible sources for new antifungal compounds with potentially novel mechanisms of action is within filamentous fungi, which have the greatest diversity of microbial life. This research proposal advances the science of metagenomics, to demonstrate Aspergillus nidulans as both a heterologous host and an initial antifungal screening target, to integrate with RNA sequencing and fungal pathogen screening of fungal biosynthetic gene clusters (BGCs) and genomes, and to discover novel antifungal chemicals and identify the best lead candidates for clinical development. Scientists at Intact Genomics, and University of Wisconsin at Madison have combined four key technological breakthroughs that result in an improved paradigm for screening small molecules. The improvements in fungal artificial chromosome (FAC) tools include: 1) an improved methodology for heterologous expression of full-length BGC-FACs; 2) the FAC heterologous strains expressing antifungal compounds also showing abnormal phenotypes; 3) new action mechanisms of abnormal phenotype BGC-FACs to be uncovered by RNA deep sequencing; 4) a panel of fungal pathogens for rapid and improved screening method to identify novel antifungal compounds. This Phase I SBIR will build upon the success of previous research by screening FACs for antifungal compounds. We will characterize the antifungal agents expressed by BGC-FAC clones and FAC libraries to determine the best lead candidates for clinical development. Lead candidates will have novel chemical structures, have high potency against multiple fungal pathogens, and minimal toxicity against human red blood cell. Each of the different technologies necessary for the proposed research has been proven effective separately; therefore, the synthesis of these different methods has a high probability of success and also represents a significant advancement for the science of antifungal discovery.

项目摘要 我们防御真菌的武器库中需要新的化合物 病原体，其中许多对现有的治疗方法越来越耐药。抗真菌药 化合物发现已被遗忘或忽视(参见2021年的评论出版物，网址为 研究战略)。新抗真菌化合物最好的可能来源之一 具有潜在的新的作用机制的是丝状真菌，它具有 微生物生命的最大多样性。这项研究建议推进了 元基因组学，以证明尼杜拉曲霉既是异源宿主，也是一种 最初的抗真菌筛选目标，结合RNA测序和真菌病原体 筛选真菌生物合成基因簇(BGC)和基因组，并发现 新的抗真菌药物和确定临床最佳候选先导药物 发展。完整基因组公司和威斯康星大学麦迪逊分校的科学家 结合了四项关键技术突破，从而提高了 筛选小分子的范例。人工真菌技术的改进 染色体(FAC)工具包括：1)针对异源基因的改进方法 全长BGC-FACS的表达；2)FAC异源菌株的表达 抗真菌化合物也表现出异常表型；3)新的作用机制 通过RNA深度测序发现表型异常的BGC-FACS；4)a 用于快速和改进的真菌病原菌筛选方法以鉴定新的 抗真菌化合物。第一阶段SBIR将在之前成功的基础上再接再厉 流式细胞仪筛选抗真菌化合物的研究。我们将描述 用BGC-FAC克隆和FAC文库表达的抗真菌药物 临床开发的最佳领跑者。领头羊候选人将拥有新的化学品 结构，对多种真菌病原体有很高的效力，毒性最小 对抗人类红血球。每一种不同的技术都是 拟议的研究已被证明单独有效；因此，合成 这些不同的方法有很高的成功几率，也代表了一种 抗真菌发现科学的重大进展。