Antifungal discovery from previously uncultivated bacteria

从以前未培养的细菌中发现抗真菌药物

• 批准号: 10693593
• 负责人: Amy Lynn Spoering
• 金额: $ 30万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-09 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693593
• 关键词: Acute; Address; Amphotericin B; Anti-Bacterial Agents; Antibiotics; Antifungal Agents; Antitubercular Agents; Bacteria; Bacterial Infections; Biological Assay; Bioreactors; COVID-19; Candida auris; Categories; Cell Line; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemical Structure; Chemicals; Classification; Clinical; Collection; Crude Extracts; Databases; Development; Disseminated candidiasis; Dose; Droughts; Drug Kinetics; Drug resistance; Environment; Fermentation; Fractionation; Goals; Growth; Growth Factor; Health care facility; Hospitalization; Hospitals; Immunocompromised Host; In Vitro; Infection; Laboratories; Lead; Liquid substance; Mammalian Cell; Maximum Tolerated Dose; Microbe; Modeling; Multi-Drug Resistance; Mus; Mycoses; Natural Compound; Natural Resources; Nursing Homes; Nystatin; Patients; Phase; Phenotype; Production; Public Health; Qualifying; Reporter; Resistance; Safety; Skin; Soil; Source; Staphylococcus aureus; Structure; Technology; Testing; Validation; Yeasts; analog; animal efficacy; combat; cytotoxicity; cytotoxicity test; drug discovery; efficacy study; falls; fungicide; fungus; in vivo; in vivo evaluation; microbial; microorganism; milligram; minimal inhibitory concentration; mortality; mouse model; mutant; novel; novel antibiotic class; novel lead compound; novel therapeutics; pathogen; pathogenic fungus; pre-clinical research; preclinical development; programs; resistance frequency; resistant strain; scale up; screening; screening program; secondary metabolite

ABSTRACT Candida auris is a multidrug-resistant yeast that can cause invasive infection and death. It spreads easily between hospitalized patients and nursing home residents. C. auris is especially hazardous to immunosuppressed patients and those hospitalized with Covid‐19. Particularly concerning, some strains of C. auris are resistant to all three major classes of antifungal drugs. As a result, this deadly pathogen has been classified as an Urgent Threat by the Centers for Disease Control (CDC), and new antifungal drugs are desperately needed. Most antifungal drugs are derived from natural compounds produced by environmental microorganisms. However, screening for antifungals from this source has fallen into disfavor, as the readily culturable microorganisms have been overmined. However, 99% of environmental microorganisms have never been screened because they will not grow under normal laboratory conditions. To address this problem, we used our iChip culturing technology to assemble a large collection of previously uncultured microorganisms. The iChip enables microorganisms to grow in their natural environment (e.g., soils), giving them access to essential growth factors. As a result, we screen microorganisms that are inaccessible to other drug discovery programs. We have used the iChip technology to discover several new antibacterial compounds such as teixobactin, which is currently in IND-enabling studies to treat drug-resistant bacterial infections. In this project we will screen our unique microbe collection for compounds that kill C. auris. In preliminary studies, we screened a small number of our iChip isolates (3,000) against C. auris. From this limited screening, we have already found five potentially novel antifungals, which we will pursue in this project. In addition, we will screen a much larger number of our isolates (30,000) to obtain additional promising compounds. Crude extracts will first be produced from fermentations and screened against C. auris. The compounds producing the antifungal activity will then be isolated from the extracts to determine their chemical novelty, potency against other important fungi (including drug-resistant strains), cytotoxicity, and frequency of resistance. Promising compounds will then be tested in a mouse efficacy model of fungal infection (disseminated candidiasis). Compounds that show good animal efficacy will be considered lead compounds and their full chemical structure will be elucidated. Our goal at the end of this project is to discover 1-2 novel lead compounds for preclinical development to combat C. auris and potentially other fungal infections.

抽象的 念珠菌Auris是一种耐多药的酵母，可引起侵入性感染和死亡。它很容易传播 在住院的患者和护士家庭居民之间。 C. Auris特别危险 免疫抑制的患者和患有Covid -19的住院患者。特别关心的是C的某些菌株。 Auris对所有三种主要类别的抗真菌药物都有抵抗力。结果，这种致命的病原体已经 疾病控制中心（CDC）和新的抗真菌药物被列为紧急威胁 迫切需要。 大多数抗真菌药物均来自环境微生物产生的天然化合物。 但是，筛查该来源的抗真菌群体已陷入不明显，因为很容易进行文化 微生物已被过度排列。但是，99％的环境微生物从未有过 筛选是因为它们不会在正常实验室条件下生长。为了解决这个问题，我们使用了 Ichip培养技术以组装大量以前未经培养的微生物。 Ichip 使微生物在自然环境（例如土壤）中生长，使它们获得基本生长 因素。结果，我们筛选了其他药物发现计划无法获得的微生物。我们有 使用ICHIP技术发现了几种新的抗菌化合物，例如Telexobactin， 目前正在研究耐药细菌感染的研究中。在这个项目中，我们将筛选我们的 杀死C. auris的化合物的独特微生物收集。 在初步研究中，我们筛选了少数Ichip分离株（3,000）针对Auris。由此 有限的筛选，我们已经找到了五个潜在的新型抗真菌剂，我们将在该项目中追求。 此外，我们将筛选大量的分离株（30,000），以获得额外的承诺 化合物。原油提取物将首先从发酵中产生，并针对Auris筛选。这 然后将从提取物中分离出产生抗真菌活性的化合物，以确定其化学物质 新颖性，对其他重要真菌（包括耐药菌株）的效力，细胞毒性和频率 反抗。然后将在真菌感染的小鼠效率模型中测试有希望的化合物（传播） 念珠菌病）。表现出良好动物效率的化合物将被视为铅化合物及其完整化合物 化学结构将被阐明。该项目结束时我们的目标是发现1-2个新颖的铅化合物 用于临床前的发育，以对抗Auris和潜在的其他真菌感染。