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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要在我们防御真菌的防御库中，社会需要新化合物病原体，其中许多越来越对现有疗法具有抗性。抗真菌复合发现已被遗忘或忽略（请参阅第2021页的评论出版物研究策略）。新抗真菌化合物的最佳来源之一具有潜在的新型作用机理在丝状真菌中，微生物生活的最大多样性。这项研究提出了发展的科学宏基因组学，以表现为异源宿主和一个初始抗真菌筛查靶标与RNA测序和真菌病原体集成筛选真菌生物合成基因簇（BGC）和基因组，并发现新型抗真菌化学物质，并确定临床的最佳铅候选者发展。完整基因组学的科学家和麦迪逊大学的威斯康星大学已经结合了四个关键的技术突破，从而改善了用于筛选小分子的范式。真菌人造的改进染色体（FAC）工具包括：1）改进的异源方法全长BGC-FAC的表达； 2）表达FAC异源菌株抗真菌化合物也表现出异常表型。 3）新的动作机制通过RNA深度测序发现的异常表型BGC-FAC； 4）快速和改进的筛选方法的真菌病原体面板以识别新颖抗真菌化合物。这阶段我将基于以前的成功通过筛选FACS的抗真菌化合物的研究。我们将表征 BGC-FAC克隆和FAC库表达的抗真菌剂以确定临床开发的最佳主要候选人。主要候选人将有新型化学物质结构，对多种真菌病原体具有很高的效力，最小的毒性反对人类红细胞。每种不同的技术拟议的研究已被证明是分别有效的。因此，合成这些不同的方法具有成功的可能性，也代表抗真菌发现科学的重大进步。