BIOSYNTHESIS APPROACH TO NOVEL BIOACTIVE AMINOCYCLITOLS

描述(申请人提供)：病原菌和真菌对当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障碍，如自身免疫性疾病(如多发性硬化症、肌萎缩侧索硬化症等)。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，在治疗各种生理疾病和感染性疾病方面具有很大的开发潜力。这是因为它们与糖类相似，糖类在生物体的结构和生理系统中以不同的方式广泛参与。在这一应用中，我们建议研究含C7N氨基环醇的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具有重要药用价值的先导化合物。这项研究将使用三种不同的化合物：(1)抗真菌药物validamcin(在吸湿链霉菌中)；(2)抗生素吡咯米星(在Nonomuraea sp.中)；以及(3)抗肿瘤药物十六烷基酯(在放线菌中)。这项研究的长期目标包括开发基于CTN氨基环醇的新药物以对抗传染病和生理障碍，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，以及对这类天然产物在自然界中的存在和分布提供见解。 该方法利用分子遗传学、酶学和化学来获取、利用和操纵CTN氨基环醇生物合成基因，这些基因指导前体的形成和其他参与定制过程的基因，以创造新的生物活性化合物。这项研究包括克隆和阐明生物合成基因簇的有效性，吡罗米星和十六烷基环己酮；阐明新发现的2-表-5-表伐洛酮途径；关键的生物合成酶的特性；以及利用所获得的信息来创造新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品家族的化学多样性。

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.