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: 7064926
• 负责人: TAIFO MAHMUD
• 金额: $ 23.3万
• 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/7064926
• 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; 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）：致病细菌和真菌中多药耐药性（MDR）的增加，与目前使用的抗生素相结合，缺乏与各种生理和调节性疾病作用的有效和安全的药物，例如自身免疫性疾病，例如自身免疫性疾病，例如多发性硬化症，多发性粘膜病，乳酸性疗法等新药物，并进行了良好的疾病癌症。 CTN氨基细胞素是一种相对较新的微生物二级代谢产物，具有巨大的潜力，可以作为各种生理疾病和传染病的药物开发。这是由于它们与糖部分的相似之处，它们在生物体的结构和生理系统中广泛涉及各种方式。在此应用中，我们建议研究含有氨基糖醇的天然产物的生物合成，并利用获得的知识来通过基于生物合成的结构修饰来开发药物重要的潜在客户。该研究将用三种不同的化合物进行：（1）抗真菌剂有效性霉素（在湿生成菌中）； （2）抗生素吡拉姆细胞蛋白（在Nonomuraea spiralis中）； （3）抗肿瘤的cetoniacytone（在放线菌中）。这项研究的长期目标包括开发新的CTN基于氨基糖醇的药物来打击传染病和生理疾病，提高产量和/或提供临床上重要的CTN氨基糖化合物的替代性生产策略，并提供有关这种自然产物的出现和分布的见解。 该方法采用分子遗传学，酶学和化学来访问，利用和操纵CTN氨基辛醇生物合成基因，这些基因引导前体形成和其他参与剪裁过程中的基因，以创建新型的生物学活性化合物。该研究包括对有效氨基霉素，吡拉藻霉素和固醇丁酮的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；并使用获得的信息来创建新型的生物活性氨基辛辛醇。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庭的化学多样性。