生物多样性,化学多样性和药物发现。

Sheo B Singh, Fernando Pelaez
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引用次数: 60

摘要

从微生物天然产物中开发的药物是现代制药公司的基础。尽管经过了几十年的研究,所有的证据都表明,一定还有许多有趣的具有潜在治疗应用的天然分子尚未被发现。任何成功开发微生物次生代谢物化学多样性的努力都需要在很大程度上依赖于对微生物多样性的良好理解,因为最大化生物多样性是最大化化学多样性的关键策略。本章概述了与这一基本原则相关的各种主题,总是与发现新的次级代谢物有关。简要回顾了更常用于天然产物发现的微生物类型,以及陆地和海洋生境作为生物活性次生代谢物生产者来源的差异。微生物多样性的概念应用于原核生物在过去几年已经发展,但最近的数据表明,细菌多样性的真正的生物地理模式的存在,这也被讨论。特别关注利用微生物多样性的现有策略,这些策略不易通过传统方法解决。这明确指的是目前试图分离和培养以前未培养的细菌,包括高通量技术的应用。同样,微生物分子生物学的进步使得宏基因组方法得以发展,即直接从环境DNA中获得生物合成途径的表达,并在合适的宿主中克隆,作为获取微生物遗传资源的另一种方式。此外,对依赖于代谢物生产者基因组学的方法进行了综述。
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Biodiversity, chemical diversity and drug discovery.

Drugs developed from microbial natural products are in the fundaments of modern pharmaceutical companies. Despite decades of research, all evidences suggest that there must remain many interesting natural molecules with potential therapeutic application yet to be discovered. Any efforts to successfully exploit the chemical diversity of microbial secondary metabolites need to rely heavily on a good understanding of microbial diversity, being the working hypothesis that maximizing biological diversity is the key strategy to maximizing chemical diversity. This chapter presents an overview of diverse topics related with this basic principle, always in relation with the discovery of novel secondary metabolites. The types of microorganisms more frequently used for natural products discovery are briefly reviewed, as well as the differences between terrestrial and marine habitats as sources of bioactive secondary metabolite producers. The concepts about microbial diversity as applied to prokaryotes have evolved in the last years, but recent data suggest the existence of true biogeographic patterns of bacterial diversity, which are also discussed. Special attention is dedicated to the existing strategies to exploit the microbial diversity that is not easy to tackle by conventional approaches. This refers explicitly to the current attempts to isolate and cultivate the previously uncultured bacteria, including the application of high throughput techniques. Likewise, the advances of microbial molecular biology has allowed the development of metagenomic approaches, i.e., the expression of biosynthetic pathways directly obtained from environmental DNA and cloned in a suitable host, as another way of accessing microbial genetic resources. Also, approaches relying on the genomics of metabolite producers are reviewed.

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