BIOSYNTHESIS APPROACH TO NOVEL BIOACTIVE AMINOCYCLITOLS

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药耐药性（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性疾病，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）和癌症迫切需要新的药物发现。 CTN氨基环醇是一类较新发现的微生物次级代谢产物，具有很大的开发潜力，可用于治疗各种生理疾病和感染性疾病。这是由于它们与糖部分的相似性，糖部分以各种方式广泛参与生物体的结构和生理系统。在本申请中，我们建议研究含C7 N氨基环醇的天然产物的生物合成，并使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物。本研究将用三种不同的化合物进行：（1）抗真菌剂井冈霉素（在S。（2）抗生素pyralomicin（在Nonomuraea spiralis中）;和（3）抗肿瘤cetoniacytone（在Actinomyces sp.中）。本研究的长期目标包括开发新的基于CTN氨基环醇的药物，以对抗感染性疾病和生理疾病，提高产量和/或提供临床重要的CTN氨基环醇化合物的替代生产策略，并提供有关这类天然产物在自然界中的发生和分布的见解。 该方法采用分子遗传学，酶学和化学来访问，利用和操纵CTN氨基环醇生物合成基因，指导前体形成和其他参与剪裁过程的基因，以产生新的生物活性化合物。该研究包括validamycin，pyralomicin和cetoniacytone的生物合成基因簇的克隆和阐明;新发现的2-epi-5-epi-valiolone途径的阐明;关键生物合成酶的表征;并使用所获得的信息来创建新的生物活性氨基环醇。从这些研究中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。

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.