Accessing and expanding microbial bioactive chemical diversity by synthetic biology and new enzymology

项目总结/摘要 天然产物（NPs）形成了一个经过验证的和卓越的新药来源，但新的 发现和有限的获得生物活性化合物是挑战目前的纳米粒子为基础的药物发现 发展先行者的要求在过去的几十年里，基因组挖掘已经成为NP发现的重要途径。这 变革性研究战略结合了功能基因组学和生物信息学， 具有潜在化学实体的基因簇（BGC）。这一战略的成功得益于越来越多的 和快速访问（Meta）基因组数据，从不同的基于规则和免费的生物信息学工具， 描绘不同化合物家族的BGC，甚至评估其新奇和潜在生物活性。 然而，基因组挖掘研究面临的一个根本挑战是如何产生足够量的 来自开采的BGC的新型生物活性NP。PI研究计划的总体目标是访问和扩展 微生物的治疗相关化学多样性直接来自它们的基因组。核心假设 这项工作的一个重要方面是，可以利用微生物基因组通过合成来生产生物活性NP和类似物， 生物学（SynBio）和酶学研究。SynBio在生产方面取得了许多显着的成功， 生物活性化合物在过去的二十年。在NP的发现中，SynBio的研究可以让表达 天然的和设计的BGC在能力机箱。平行地，微生物NP的生物合成富集有 功能多样的酶，其提供使能策略以产生生物活性物质的关键中间体和类似物， NP。为了实现这一目标并检验假设，本次更新将追求两个相互关联的研究方向。 方向1将侧重于从较少开发的资源中发现和生产生物活性纳米颗粒，特别是 海洋夹带。为了最大限度地取得成功，我们的SynBio研究将开发和使用多种 细菌门本提案的研究方向2将发现并综合表征具有重要意义的 酶使用不同的方法，帮助获得和扩大治疗相关的 NP的化学多样性。在方向1中发现的新酶将在方向2中表征，然后可以 支持在方向1中挖掘新的BGC，从而实现两者的紧密集成和相互支持 方向这两个方向结合起来，可以提供创新战略，使有效利用 来自研究较少的微生物基因组的生物活性纳米颗粒。这些研究也可以促进转型 NP研究从小规模的追求到基于基因组的高通量奋进，因此支持 基于NP的药物研究的范式转变。

Project Summary/Abstract Natural products (NPs) form a validated and preeminent source of new drug leads, but the low rate of new discoveries and the limited access to bioactive compounds are challenging current NPs-based drug discovery and development. Over the past decades, genome mining has become an important way for NP discovery. This transformative research strategy combines functional genomics and bioinformatics to associate biosynthetic gene clusters (BGCs) with potential chemical entities. The success of this strategy is supported by increasing and rapid access to (meta)genomic data, from which diverse rule-based and -free bioinformatics tools enable depicting the BGCs of different compound families and even assessing their novelty and potential bioactivity. However, a fundamental challenge faced by genome mining research is how to produce sufficient amounts of novel, bioactive NPs from mined BGCs. The overall goal of the PI's research program is to access and expand the therapeutically relevant chemical diversity of microbes directly from their genomes. The central hypothesis of this work is that microbial genomes can be exploited to produce bioactive NPs and analogs through synthetic biology (SynBio) and enzymology research. SynBio has achieved many notable successes in the production of bioactive compounds over the past two decades. In the NP discovery, SynBio studies can allow the expression of natural and designed BGCs in capable chasses. In parallel, the biosynthesis of microbial NPs is enriched with functionally diverse enzymes that lend enabling strategies to produce key intermediates and analogs of bioactive NPs. To achieve the goal and test the hypothesis, this renewal will pursue two interlinked research directions. Direction 1 will focus on the discovery and production of bioactive NPs from less-explored resources, particularly in marine entrainment. To maximize the success, our SynBio research will develop and use chasses of multiple bacterial phyla. Research direction 2 of this proposal will discover and characterize synthetically significant enzymes using a diverse set of approaches, aiding the access and expansion of therapeutically relevant chemical diversity of NPs. New enzymes found in Direction 1 will be characterized in Direction 2 and can then support the mining of new BGCs in Direction 1, leading to tight integration and mutual support of the two directions. Together, these two directions can afford innovative strategies that enable the effective exploitation of bioactive NPs from the genomes of less-studied microbes. These studies can also boost the transformation of NP research from small-scale pursuits to a genome-based high-throughput endeavor, therefore supporting the paradigm shift in NP-based drug research.