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.

项目摘要 糖模拟物具有重要的生物活性。其中许多目前用于 在诊所中作为抗菌剂（例如，链霉素，庆大霉素，新霉素），抗病毒药（例如，奥司他韦，帕拉米韦， 恩替卡韦）和抗糖尿病药物（例如，阿卡波糖、伏格列波糖）。在天然存在的糖模拟物中， 氨基环庚醇，其含有类似核糖的五元环醇单元（核糖模拟物）。然而，在这方面， 由于它们的广谱毒性和/或低产量，尚未开发出用于临床应用的药物。 因此，解决这些局限性可能会提供新的途径，以充分发挥其潜力， 毒品线索该项目的长期目标是了解核糖模拟天然产物的生物合成 产品和开发新的基于Ribomimetic的药物来对抗传染病。在本提案中，我们将 集中精力研究含核糖模拟物的抗生素帕塔霉素的生物合成， 开发新的帕他霉素类似物作为抗细菌、病毒和疟疾寄生虫的先导药物。我们 初步数据表明，帕他霉素核心结构的形成涉及高度不寻常的离散 聚酮酶、广谱糖基转移酶和自由基SAM酶。我们还发现 由于许多混杂的抗生素的活性， 定制酶此外，我们还开发了遗传、合成和化学-酶促策略 （涉及广谱酮脂酰-ACP合酶（KAS）III样蛋白）以产生新的帕塔霉素类似物 和其它拟核糖化合物，其中一些具有改进的生物学特性。在此，我们建议：1） 表征离散PKS蛋白的协调功能和酰基载体的不寻常糖基化 蛋白（ACP）结合的聚酮中间体; 2）破译核糖模拟核心的形成模式， 预测通过由自由基化学介导的独特生物转化发生;和3）发展和 测试新的拟核糖抗生素的抗感染活性。这项研究的成功完成将推动 在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，特别是抗菌药、抗病毒药和抗寄生虫药。