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.

摘要 耳念珠菌是一种多药耐药酵母菌，可导致侵入性感染和死亡。它很容易传播 住院病人和疗养院居民之间的联系C.耳特别危险， 免疫抑制患者和因Covid-19住院的患者。特别值得关注的是，一些C. 耳对所有三种主要类型的抗真菌药物都有抗性。因此，这种致命的病原体 被疾病控制中心（CDC）列为紧急威胁，新的抗真菌药物正在 迫切需要的。 大多数抗真菌药物来自环境微生物产生的天然化合物。 然而，从这种来源筛选抗真菌药物已经失宠，因为容易培养的 微生物已经被过度开采。然而，99%的环境微生物从未被 因为它们在正常的实验室条件下不会生长。为了解决这个问题，我们使用了 iChip培养技术，用于组装大量以前未培养的微生物。iChip 使微生物能够在其自然环境中生长（例如，土壤），使它们获得必要的生长 因素因此，我们筛选出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，如teixobactin， 目前在IND使能研究中用于治疗耐药细菌感染。在这个项目中，我们将筛选我们的 独特的微生物收集的化合物，杀死C。耳。 在初步研究中，我们筛选了少量的iChip分离株（3，000株），以对抗C。耳。从这个 在有限的筛选中，我们已经发现了五种潜在的新型抗真菌药物，我们将在本项目中继续研究。 此外，我们将筛选更多的分离株（30，000），以获得更多有希望的分离株。 化合物.粗提物将首先从发酵中产生，并针对C.耳。的 然后将产生抗真菌活性的化合物从提取物中分离出来， 新奇、对其他重要真菌（包括耐药菌株）的效力、细胞毒性和 阻力然后将在真菌感染（播散性感染）的小鼠功效模型中测试有希望的化合物。 念珠菌病）。显示出良好的动物功效的化合物将被认为是先导化合物，并且它们的全部 将阐明化学结构。我们的目标是在这个项目的最后发现1-2个新的先导化合物 用于临床前开发以对抗C.耳和潜在的其他真菌感染。