Isolating novel fungi for antibiotic discovery

分离新真菌以发现抗生素

• 批准号: 8081762
• 负责人: Losee Lucy Ling
• 金额: $ 99.98万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081762
• 关键词: Acinetobacter; Actinobacteria class; Acute; Agar; Animal Model; Animal Testing; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Architecture; Biodiversity; Biological; Biological Assay; Biological Testing; Bioterrorism; Burkholderia; Cephalosporins; Clinical; Collection; Communicable Diseases; Community Hospitals; Development; Engineering; Enterobacter; Escherichia coli; Evaluation; Frequencies; Goals; Gram-Negative Bacteria; Growth; Human; Hyphae; In Situ; In Vitro; Infection; Klebsiella; Klebsiella pneumonia bacterium; Laboratories; Lactams; Lead; Lung; Maximum Tolerated Dose; Membrane; Methods; Molecular; Multi-Drug Resistance; Mus; New Agents; Organism; Pharmaceutical Preparations; Phase; Pneumonia; Probability; Property; Pseudomonas; Public Health; Resistance; Resistance development; Resources; Roentgen Rays; Running; Septicemia; Sequence Analysis; Serum; Soil; Solid; Solutions; Source; Staphylococcus aureus; Sterility; Structure; Technology; Testing; Toxic effect; United States; Validation; Vancomycin resistant enterococcus; Work; antimicrobial; antimicrobial drug; base; biodefense; cytotoxicity; drug development; drug discovery; fungus; genome sequencing; in vivo; meetings; methicillin resistant Staphylococcus aureus; microbial; microorganism; new technology; novel; pathogen; programs; public health relevance; research study; resistance mutation; resistant strain

DESCRIPTION (provided by applicant): The goal of this project is to discover and develop novel broad-spectrum antibiotics acting against critically important human pathogens. The unmet need is especially acute for Gram-negative pathogens, where we are rapidly running out of options for treating multidrug resistant species of Pseudomonas, Acinetobacter, Burkholderia, Klebsiella and Enterobacter. This is a challenging goal, since the last novel class of broad-spectrum antibiotics was discovered 40 years ago. Currently, there are no broad-spectrum leads in the global pipeline of drug discovery, according to the review of this important subject at the last ICAAC meeting. The main barrier to progress in antimicrobial drug discovery is the lack of sources for novel compounds. NovoBiotic has a proprietary technology capable of meeting this challenge. We are obtaining new antimicrobials from a previously inaccessible source - uncultured fungi. In Phase I, we developed a trap for specific capture and growth of uncultured fungi. Many antimicrobials, including ?-lactams and cephalosporins derive from culturable representatives of this group of microorganisms. The trap consists of two layers of sterile agar sandwiched between semi-permeable membranes that is inserted into soil. Fungi produce hyphae which enable them to penetrate into the trap through the pores in the membrane, into the upper layer of agar and form pure colonies. Many uncultured species that initially grow in situ are then capable of growing under standard laboratory conditions in vitro. The aims of Phase I were to assemble a collection of 200 fungi using the trap method, screen them for antimicrobial activity and dereplicate 25 of them. We achieved these milestones and discovered a novel broad- spectrum antimicrobial, Novo15, from an uncultured fungus only distantly related to known organisms. In Phase II we will validate the compounds discovered in Phase I in in vitro biological assays and animal models of S. aureus and K. pneumonia pulmonary infection. Also, we will isolate and screen an additional 250,000 fungal strains from the trap (Aim 1), validate potential leads using in vitro biological tests and determine the structure of promising compounds (Aim 2), and perform animal tests on 10 novel compounds (Aim 3). The end result of Phase II will be 2-3 validated, novel broad-spectrum antimicrobials. These will be developed into drugs in the next phase of the program. PUBLIC HEALTH RELEVANCE: There is increasing public health concern about the ability of currently available antibiotics to keep pace with evolving microbial resistance; naturally acquired in the case of community and hospital based infections, and potentially engineered in the case of bioterror agents. One solution to this problem is the development of new antibiotics. The purpose of this project is to use our new technology to identify new classes of antibiotics with broad-spectrum activity against both conventional and biodefense pathogens.

描述（由申请人提供）：该项目的目标是发现和开发针对极其重要的人类病原体的新型广谱抗生素。对于革兰氏阴性病原体来说，未满足的需求尤其严重，我们正在迅速耗尽治疗假单胞菌、不动杆菌、伯克霍尔德杆菌、克雷伯氏菌和肠杆菌等多重耐药菌种的选择。 这是一个具有挑战性的目标，因为最后一类新型广谱抗生素是 40 年前发现的。根据上次 ICAAC 会议对这一重要主题的审查，目前全球药物发现渠道中尚无广谱先导药物。抗菌药物发现进展的主要障碍是缺乏新化合物的来源。 NovoBiotic 拥有能够应对这一挑战的专有技术。我们正在从以前无法获得的来源——未培养的真菌中获得新的抗菌剂。在第一阶段，我们开发了一种用于特定捕获和生长未培养真菌的陷阱。许多抗菌剂，包括β-内酰胺类和头孢菌素类，均源自该类微生物的可培养代表。该陷阱由夹在插入土壤的半透膜之间的两层无菌琼脂组成。真菌产生菌丝，使它们能够通过膜上的孔渗透到陷阱中，进入琼脂上层并形成纯菌落。许多最初在原位生长的未培养物种随后能够在标准实验室条件下在体外生长。 第一阶段的目标是使用诱捕法收集 200 种真菌，筛选它们的抗菌活性，并消除其中 25 种的复制。我们实现了这些里程碑，并从一种与已知生物体只有远亲关系的未培养真菌中发现了一种新型广谱抗菌剂 Novo15。在第二阶段，我们将在金黄色葡萄球菌和肺炎克雷伯菌肺部感染的体外生物测定和动物模型中验证第一阶段发现的化合物。此外，我们将从陷阱中分离和筛选另外 250,000 个真菌菌株（目标 1），使用体外生物测试验证潜在线索并确定有前景的化合物的结构（目标 2），并对 10 种新型化合物进行动物测试（目标 3）。 II 期的最终结果将是 2-3 种经过验证的新型广谱抗菌药物。这些将在该计划的下一阶段开发成药物。 公共卫生相关性：公众健康越来越关注当前可用抗生素是否能够跟上不断变化的微生物耐药性；在社区和医院感染的情况下自然获得，在生物恐怖制剂的情况下可能被设计。解决这个问题的一个办法是开发新的抗生素。该项目的目的是利用我们的新技术来识别对传统病原体和生物防御病原体具有广谱活性的新型抗生素。