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Targeted natural product diversification to identify novel antibacterial agents

有针对性的天然产品多样化以确定新型抗菌剂

基本信息

批准号：
8955586
负责人：
Erin Elizabeth Carlson
金额：
$ 110.34万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8955586
关键词：
Targeted natural product diversification identify

项目摘要

Abstract With the advent of the “age of antibiotics” in the 1940s, many believed that we had conquered these dangerous microbes. However, it quickly became apparent that the ability of bacteria to evolve resistance had been sorely underestimated and today, infectious diseases are the second-leading cause of death worldwide and the third-leading cause of mortality in economically advanced countries. The ever-growing and significant problem of antibacterial resistance requires discovery of new leads. However, identification of the next generations of antibiotics will necessitate a change in the current drug discovery paradigm. Pursuit of compounds that function through the commonly targeted mechanisms of action will not yield the combination of antibiotic potency and long-term efficacy necessary to combat resistant organisms. In fact, compounds that attack microbes through multiple, simultaneous mechanisms will be essential to anti-infective development. Given the anticipated therapeutic benefits of modulation of bacterial virulence and host innate immunity, we will focus our efforts on the identification of compounds possessing these activities. The proposed work will facilitate discovery of antibacterial agents by transforming the ways in which natural product are both explored and exploited. Although natural products have historically provided the majority of treatments for infectious disease, the exceptional potential of nature's molecular repertoire is still largely untapped because the current approaches used in their discovery are fundamentally limited in both scope and power. Thus, there is tremendous need for development of methods that can investigate the confluence of natural product space and antibiotic space. To accomplish this goal, we will apply our chemoselective natural products isolation technology, which facilitates compound enrichment by reversible capture of a specified functional group class onto solid support, to the exploration of natural products. This tagging technology will also be utilized in the creation of a novel natural product diversification strategy. Existing approaches for natural product library generation depend upon the functionalization of discreet natural products, a process that is influenced by both the choice of lead structure and preconceptions about how derivatization will affect activity. We will devise a method for discovery that is not biased by existing hypotheses. Following chemoselective immobilization, derivatization of the natural products will be performed in an unbiased fashion; that is, we will perform functionalization reactions without prior knowledge of the natural product structures. Derivatization of the natural products with targeting agents, such as a virulence mechanism inhibitor, will yield a diverse library of compounds containing a known bioactive portion and a novel natural product moiety. This approach will facilitate the identification of dual-function compounds with enhanced anti-infective properties.

摘要随着20世纪40年代“抗生素时代”的到来，许多人认为我们已经征服了这些危险的微生物。然而，很快就变得明显的是，细菌进化抗药性的能力传染病被严重低估了，今天，传染病是全球第二大死亡原因在经济发达国家，这是导致死亡的第三大原因。不断增长和意义重大的抗菌素耐药性的问题需要发现新的线索。然而，识别下一个一代又一代的抗生素将需要改变目前的药物发现范式。追求通过共同靶向作用机制发挥作用的化合物不会产生对抗耐药生物体所需的抗生素效力和长期疗效。事实上，这种化合物通过多个同时的机制攻击微生物将是抗感染发展的关键。考虑到调节细菌毒力和宿主天然免疫的预期治疗益处，我们将将我们的努力集中在识别具有这些活性的化合物上。这项拟议的工作将通过改变自然产品既被开发，又被开发。尽管天然产品在历史上提供了大多数传染病的治疗方法，大自然的分子宝库的特殊潜力仍然是很大程度上没有开发，因为目前用于发现它们的方法从根本上限制在两个方面范围和权力。因此，非常需要开发能够调查自然产品空间和抗生素空间的融合。为了实现这一目标，我们将应用我们的化学选择性天然产物分离技术，便于化合物的可逆浓缩将指定的官能团类捕获到坚实的支撑物上，以天然产物为探索对象。这标签技术还将被用于创建一种新的天然产品多样化战略。现有的自然产品库生成方法依赖于Discreet Natural的功能化产品，这一过程既受到引线结构选择的影响，也受到对如何衍生化会影响活性。我们将设计出一种不受现有技术影响的发现方法假设。在化学选择性固定化之后，将进行天然产物的衍生化以一种不偏不倚的方式；也就是说，我们将在不事先知道自然的产品结构。天然产物与靶向剂的衍生化，如毒力机制抑制剂，将产生一个不同的化合物文库，其中包含一个已知的生物活性部分和一个新的天然产物部分。这一方法将有助于双功能化合物的鉴定增强的抗感染性能。