Deciphering complex machineries that produce ribosomally synthesised natural products

人类社会不断需要新药，例如，为了赢得军备竞赛，出现了具有抗生素耐药性的超级细菌。从历史上看，天然产品一直是我们获得新型生物活性化合物的最佳来源(例如，最初从真菌霉菌中分离出来的青霉素)。事实上，在癌症和微生物学的重要领域，市场上几乎75%的药物都是从植物、海洋生物或微生物中分离出来的天然产物，如细菌。细菌制造这些受欢迎的天然产品的能力是在它们的基因组中编码的。超过300,000个细菌基因组已经被测序并公开提供。它们提供了数百万未知天然产品的数据，其中一些将被证明是治愈疾病的关键。我们面临的问题是，不可能解决所有这些问题，所以我们需要做出明智的选择。核糖体合成和翻译后修饰多肽(Ripps)是由许多不同类型的细胞产生的天然产物。RIPPS具有广泛的生物活性，包括抗病毒、抗肿瘤和抗生素。它们还被认为与抗真菌和止痛活动有关。由于其多种生物活性，各种RIPP衍生物目前正在接受治疗评估，RIPP总体上是许多生物技术初创公司的重点，他们的目标是试图将它们作为未来的药物。RIPP是由细胞的核糖体构成的，核糖体是制造蛋白质和较短氨基酸链的分子机器。RIPPS以氨基酸短链的形式开始，然后被细胞内的一系列酶修饰，产生最终的生物活性产品。由修饰酶引入的化学和结构多样性使可用产物的种类远远超出了核糖体可获得的20个氨基酸。这种显着的化学和结构多样性的结果是，仅凭细菌基因组序列预测RIPP结构在很大程度上是不可能的。我们需要更好地了解参与其生物合成的酶，以做出可靠的预测，从而确定工作路径的优先顺序。对RIPP生物合成中所涉及的酶的详细了解将解决这一问题，并将使我们和其他人能够改进酶的生物工程，以改善其功能，并诱导它们制造更多种类的有用的、具有医学价值的产品。它还将解决天然产品的供应问题，启发其生产的新方法，并且至关重要的是，为药物开发提供合理的化合物修饰过程。我们选择了两个参与RIPPS生物合成的蛋白质复合体，它们具有机械上的共同之处，而不是化学上的共同点。这两个络合物将使用最先进的技术进行研究，这些技术以前从未被结合起来研究RIPP络合物。这种方法和产生的结果将改变我们对选定的RIPP生物合成复合体的理解，并有助于释放它们的全部潜力。我们预计，这项工作的结果将使研究实验室和生物制药公司能够生产世界需要和期望的更多药物化合物。

Human society is in constant need of new drugs, for example to win the arms race with emerging antibiotic resistant superbugs. Historically, natural products have been our best source of novel, bioactive compounds (for example, penicillin which was first isolated from a fungal mold). In fact, in the important fields of cancer and microbiology, almost 75% of all drugs on the market are natural products isolated from plants, marine organisms or microorganisms, such as bacteria. The ability of bacteria to make these sought-after natural products is encoded in their genomes. Over 300,000 bacterial genomes have been sequenced and made publicly available. They provide data for millions of unknown natural products, some of which will prove essential to curing diseases. The problem we face is that it is impossible to work on all of them, so we need to make smart choices.Ribosomally synthesized and post-translationally modified peptides (RiPPs) are natural products made by many different types of cells. RiPPs display a wide variety of promising bioactivities, including anti-viral, anti-tumor and antibiotic. They have also been linked to anti-fungal and painkilling activities. As a result of their manifold bioactivities, a variety of RiPP derivatives are currently undergoing therapeutic evaluation and RiPPs in general are the focus of many biotech start-up companies whose aim is to try to harness them as medicines of the future. RiPPs are made by the cell's ribosomes - the molecular machines that make proteins and shorter chains of amino acids. RiPPs start off as short chains of amino acids that are then modified by a cascade of enzymes within the cell to produce the final bioactive product. The chemical and structural diversity introduced by the modifying enzymes expands the available repertoire of products far beyond the 20 amino acids that would otherwise be available from the ribosome.A result of this remarkable chemical and structural diversity is that the prediction of RiPP structures from the bacterial genome sequence alone is largely impossible. We need a much better understanding of the enzymes involved in their biosynthesis to make robust predictions and thus prioritize pathways to work on. A detailed understanding of the enzymes involved in RiPP biosynthesis will address this issue, and will allow us and others to improve the bioengineering of enzymes in order to improve their function and to induce them to make an even wider variety of useful medically valuable products. It will also address problems with the supply of natural products, inspire new methods for their production and, crucially, inform the process of rational compound modifications for drug development.We have selected two protein complexes involved in the biosynthesis of RiPPs that share mechanistic but not chemical commonalities. These two complexes will be investigated using state-of-the art techniques that have never been combined to study RiPP complexes before. This approach and the results generated will provide a step-change in our understanding of the selected RiPP biosynthetic complexes and be instrumental in unlocking their full potential. We expect that the results of this work will enable research laboratories and biopharmaceutical companies to produce more of the drug compounds that the world needs and expects.