BIOSYNTHESIS APPROACH TO NOVEL BIOACTIVE AMINOCYCLITOLS

新型生物活性氨基环醇的生物合成方法

• 批准号: 6897295
• 负责人: TAIFO MAHMUD
• 金额: $ 23.53万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897295
• 关键词: Actinomyces; Streptomyces; analog; antibiotics; antifungal antibiotics; antineoplastics; bacteria; biological products; biosynthesis; biotechnology; biotherapeutic agent; drug design /synthesis /production; enzyme activity; enzymes; gene expression; genetic manipulation; genetic regulation; microorganism culture; microorganism metabolism; molecular cloning; molecular genetics; mutant; nucleic acid sequence

DESCRIPTION (provided by applicant): The increase of multi drug resistance (MDR) among pathogenic bacteria and fungi towards currently used antibiotics coupled with the lack of effective and safe medications to combat various physiological and regulatory disorders such as autoimmune diseases (e.g., multiple sclerosis, amyotrophic lateral sclerosis, etc.) and cancer urgently require new drug discovery. The CTN aminocyclitols, a relatively newly recognized class of microbial secondary metabolites, has great potential to be developed as drugs for various physiological disorders and infectious diseases. This is due to their resemblance to sugar moieties, which are widely involved in various ways in structural and physiological systems in living organisms. In this application, we propose to study the biosynthesis of C7N aminocyclitol-containing natural products and to use the knowledge obtained to develop pharmaceutically important leads via biosynthetic-based structure modifications. The study will be carried out with three different compounds: (1) the antifungal agent validamycin (in S. hygroscopicus); (2) the antibiotic pyralomicin (in Nonomuraea spiralis); and (3) the anti-tumor cetoniacytone (in Actinomyces sp.). The long-term objectives of this study include developing new CTN aminocyclitol-based drugs to combat infectious diseases and physiological disorders, improving production yields and/or providing alternative production strategies of clinically important CTN aminocyclitol compounds, and providing insights about the occurrence and distribution of this class of natural products in nature. The approach employs molecular genetics, enzymology, and chemistry to access, utilize and manipulate CTN aminocyclitol biosynthesis genes that direct precursor formation and other genes involved in the tailoring processes to create novel biologically active compounds. The study includes cloning and elucidation of the biosynthetic gene clusters of validamycin, pyralomicin, and cetoniacytone; elucidation of the newly discovered 2-epi-5-epi-valiolone pathway; characterization of the key biosynthetic enzymes; and use the information obtained to create novel bioactive aminocyclitols. The knowledge and methods that arise from these studies will be directly applicable to expanding the chemical diversity in other families of bioactive natural products.

描述（由申请人提供）：病原菌和真菌对目前使用的抗生素的多重耐药性（MDR）增加，加上缺乏有效和安全的药物来对抗各种生理和调节疾病，例如自身免疫性疾病（例如多发性硬化症） 、肌萎缩侧索硬化症等）和癌症迫切需要新药发现。 CTN氨基环醇是一类相对较新认识的微生物次级代谢产物，具有开发为治疗各种生理疾病和传染病的药物的巨大潜力。这是因为它们与糖部分相似，糖部分以各种方式广泛参与生物体的结构和生理系统。在此应用中，我们建议研究含 C7N 氨基环醇天然产物的生物合成，并利用所获得的知识通过基于生物合成的结构修饰来开发药学上重要的先导化合物。该研究将使用三种不同的化合物进行：（1）抗真菌剂井冈霉素（在吸湿链球菌中）； (2)抗生素pyralomicin（在Nonomuraeaspiralis中）； (3) 抗肿瘤 cetoniacytone（放线菌属中）。这项研究的长期目标包括开发新的基于 CTN 氨基环醇的药物来对抗传染病和生理紊乱，提高产量和/或提供临床上重要的 CTN 氨基环醇化合物的替代生产策略，并提供有关 CTN 氨基环醇化合物的发生和分布的见解。这类天然产物存在于自然界中。 该方法采用分子遗传学、酶学和化学来获取、利用和操纵指导前体形成的 CTN 氨基环醇生物合成基因以及参与定制过程的其他基因，以创建新型生物活性化合物。该研究包括有效霉素、pyralomicin 和 cetoniacytone 生物合成基因簇的克隆和阐明；阐明新发现的 2-epi-5-epi-valiolone 途径；关键生物合成酶的表征；并利用获得的信息来创造新型的生物活性氨基环醇。这些研究产生的知识和方法将直接适用于扩大其他生物活性天然产物家族的化学多样性。