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.

项目概要社会需要我们的真菌防御库中的新化合物病原体，其中许多对现有疗法的抵抗力越来越强。抗真菌剂化合物的发现已被遗忘或忽视（请参阅 2021 年评论出版物，网址为研究策略）。新型抗真菌化合物的最佳来源之一丝状真菌具有潜在的新颖作用机制，其具有微生物生命的最大多样性。这项研究提案推进了科学宏基因组学，证明构巢曲霉既是异源宿主又是初步抗真菌筛选目标，与 RNA 测序和真菌病原体整合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最佳先导候选药物发展。 Intact Genomics 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，从而改进了筛选小分子的范例。人工真菌的改进染色体（FAC）工具包括：1）改进的异源方法全长 BGC-FAC 的表达； 2) FAC异源菌株表达抗真菌化合物也表现出异常表型； 3）新的行动机制通过 RNA 深度测序发现异常表型 BGC-FAC； 4）一个真菌病原体小组，用于快速和改进的筛选方法，以识别新的抗真菌化合物。第一阶段 SBIR 将建立在之前的成功基础上通过筛选 FAC 中的抗真菌化合物进行研究。我们将表征 BGC-FAC克隆和FAC文库表达的抗真菌剂，以确定临床开发的最佳主要候选者。主要候选人将拥有新型化学物质结构，对多种真菌病原体具有高效力，并且毒性最小对抗人类红细胞。每种不同的技术都需要所提出的研究已被单独证明是有效的；因此，合成这些不同的方法成功的可能性很高，也代表了抗真菌发现科学的重大进步。