Biosynthetic studies and development of ribomimetic-based anti-infectives

基于核糖体的抗感染药物的生物合成研究和开发

• 批准号: 10079458
• 负责人: TAIFO MAHMUD
• 金额: $ 35.8万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-08 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079458
• 关键词: 4-Aminobenzoic Acid; Acarbose; Acyl Carrier Protein; Acyltransferase; Address; Anabolism; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Antidiabetic Drugs; Antifungal Agents; Antimalarials; Antiparasitic Agents; Antiviral Agents; Bacteria; Binding Proteins; Biological; Biological Assay; Chemicals; Chemistry; Clinic; Clinical; Collaborations; Communicable Diseases; Data; Development; Enzymes; Gene Silencing; Genetic; Gentamicins; Goals; Health; Human; In Vitro; Institutes; Investigation; Knowledge; Libraries; Malaria; Mediating; Medical center; Metabolic Biotransformation; Natural Products; Neomycin; Oregon; Oseltamivir; Pactamycin; Parasites; Pathway interactions; Pharmaceutical Preparations; Plants; Positioning Attribute; Production; Property; Proteins; Recombinants; Research; Ribose; Scientific Advances and Accomplishments; Skeleton; Streptomyces; Streptomycin; Structure; System; Testing; Toxic effect; Translational Research; Virus; Work; analog; anti-hepatitis B; anti-influenza; anti-influenza drug; antimicrobial; antimicrobial drug; base; combat; cytotoxicity; drug discovery; entecavir; experience; glycosylation; glycosyltransferase; high throughput screening; holo-(acyl-carrier-protein) synthase; improved; in vitro activity; insight; mimetics; multidisciplinary; neplanocin A; novel therapeutics; polyketide synthase; reconstitution; research and development; sugar; thioester; validamycins; voglibose

PROJECT SUMMARY Sugar mimetics have long been known for their important biological activities. Many of them are currently used in clinics as antimicrobials (e.g., streptomycin, gentamycin, neomycin), antivirals (e.g., oseltamivir, peramivir, entecavir), and anti-diabetics (e.g., acarbose, voglibose). Among naturally-occurring sugar mimetics are the aminocyclopentitols, which contain a five-membered cyclitol unit resembling ribose (ribomimetics). However, due to their broad-spectrum toxicity and/or low production yield, none has yet been developed for clinical use. Therefore, addressing these limitations may provide new paths to the exploitation of their full potential as new drug leads. The long-term goals of this project are to understand the biosynthesis of ribomimetic natural products and to develop new ribomimetic-based drugs to combat infectious diseases. In this proposal, we will focus effort on interrogating the biosynthesis of the ribomimetic-containing antibiotic pactamycin and developing new pactamycin analogs as drug leads against bacteria, viruses, and malarial parasites. Our preliminary data suggest that formation of the pactamycin core structure involves highly unusual discrete polyketide synthases, a broad-spectrum glycosyltransferase, and a radical SAM enzyme. We also found that the tailoring pathway to pactamycin is exceptionally perplexing, due to the activity of numerous promiscuous tailoring enzymes. Furthermore, we have developed genetic, synthetic, and chemo-enzymatic strategies (involving a broad-spectrum ketoacyl-ACP synthase (KAS) III-like protein) to produce new pactamycin analogs and other ribomimetic compounds, some of which have improved biological properties. Here, we propose to: 1) characterize the coordinate function of discrete PKS proteins and the unusual glycosylation of an acyl carrier protein (ACP)-bound polyketide intermediate; 2) decipher the mode of formation of the ribomimetic core, which is predicted to take place via a distinctive biotransformation mediated by radical chemistry; and 3) develop and test new ribomimetic antibiotics for anti-infective activities. Successful completion of this research will advance scientific knowledge and technical capability in the field, and will address the current slow pace of progress in the discovery of new anti-infective drugs, particularly antibacterial, antiviral, and anti-parasitic agents.

项目总结 糖的模拟物因其重要的生物活性而广为人知。他们中的许多人目前正在使用 在临床上作为抗菌剂(例如链霉素、庆大霉素、新霉素)、抗病毒药物(例如奥司他韦、帕拉米韦、 恩替卡韦)和抗糖尿病药物(如阿卡波糖、伏格列波糖)。在自然产生的糖的模拟物中有 氨基环戊醇，它含有一个类似核糖的五元环戊醇单元(核仿学)。然而， 由于它们的广谱毒性和/或产量低，目前还没有开发出用于临床的药物。 因此，解决这些限制可能会提供新的途径，以充分挖掘它们的新潜力 毒品线索。这个项目的长期目标是了解核仿生天然产物的生物合成。 并开发新的核仿制药物，以对抗传染病。在这项提案中，我们将 重点调查含有核素仿制药的抗生素帕他霉素和 开发新的帕他霉素类似物作为治疗细菌、病毒和疟疾寄生虫的药物。我们的 初步数据表明，帕他霉素核心结构的形成涉及非常不寻常的离散 聚酮合成酶，一种广谱糖基转移酶和一种自由基SAM酶。我们还发现， 由于许多混杂分子的活动，合成帕他霉素的途径异常令人困惑。 剪裁酵素。此外，我们还开发了遗传、合成和化学-酶策略。 (涉及广谱酮酰-ACP合成酶(KAS)III类蛋白)产生新的帕他霉素类似物 以及其他核仿生化合物，其中一些具有更好的生物学特性。在此，我们建议：1) 表征离散PKS蛋白的配位功能和一个酰基载体的异常糖基化 蛋白质(ACP)结合的聚酮中间体；2)破译仿核核心的形成方式， 预计将通过自由基化学介导的独特生物转化发生；以及3)发展和 测试新的核仿制抗生素的抗感染活性。这项研究的成功完成将推动 该领域的科学知识和技术能力，并将解决目前进展缓慢的问题 新的抗感染药物的发现，特别是抗菌、抗病毒和抗寄生虫剂。