Directed posttranslational modifications for drug design and discovery

描述(申请人提供)：最近人们认识到，核糖体多肽天然产物(RIPP)是地球上主要的生物活性天然产物之一。这些化合物几乎普遍存在于细菌中，它们在细菌中扮演着不同的角色，包括群体信号、辅因子合成和化学防御。最常见的是，RIPPS具有很强的抗菌活性。他们是现代药物发现和开发的关键参与者。也许更重要的是，Ripps提供了一个巨大的翻译后机器仓库，可以用来设计类似药物的化合物。它们很容易被操纵来进行合理的工程设计和所需性能的优化。在这项提案中，我们将使用这种多样化的RIPP生物合成机制来更好地了解翻译后酶，优化和设计生产平台，并开发技术，以更好地利用这些复杂的途径来设计和发现新的抗生素。我们的具体目标是：1)使用化学、生化和遗传方法表征独特的RIPP翻译后酶；2)促进异源宿主中化合物的生产和类似物的合成；3)通过实施新的生物检测方法发现新的抗生素。

DESCRIPTION (provided by applicant): It has recently become appreciated that ribosomal peptide natural products (RiPPs) represent one of the major groups of bioactive natural products on Earth. The compounds are found nearly universally in bacteria, where they place diverse roles including quorum signaling, cofactor synthesis, and chemical defense. Most commonly, RiPPs exhibit potent antibiotic activity. They are key players in modern drug discovery and development. Perhaps more importantly, RiPPs present an enormous storehouse of posttranslational machinery that can be used to design drug-like compounds. They are readily manipulated for the rational engineering and optimization of desired properties. In this proposal, we will use this diverse RiPP biosynthetic machinery to better understand posttranslational enzymes, to optimize and engineer production platforms, and to develop technologies to better harness these complex pathways in the design and discovery of new antibiotics. Our specific aims are to: 1) Characterize unique RiPP posttranslational enzymes using chemical, biochemical, and genetic methods; 2) Improve compound production and analog synthesis in heterologous hosts; 3) Discover new antibiotics by implementing novel bioassays.