Harnessing the biosynthetic potential of bacteria to produce ribosomally synthesised natural products

细菌能制造出数量惊人的化合物，这些化合物对各种医疗和农业用途都是无价的，包括抗生素、抗真菌剂、抗癌化合物和杀虫剂。事实上，临床上使用的大多数抗生素都来自土壤中的细菌。这种生产这些具有生物活性的天然产物的能力源于分子为生产者提供的进化优势。例如，细菌已经进化出产生强效抗生素的能力，以杀死竞争的邻近微生物。最近多重耐药细菌感染上升的危机意味着迫切需要发现新的抗生素。我们相信还有许多新的抗生素有待从细菌中发现，但现有的发现方法缺少了许多隐藏的分子，我们称之为“代谢暗物质”。这些天然产物是由细菌基因组中的基因（DNA）编码的一系列酶（蛋白质）的作用产生的。现在已经对数十万种细菌基因组进行了测序。研究人员已经开发出了一些方法，可以根据这些基因组数据预测细菌应该能够制造出哪些化合物（“基因组挖掘”）。这表明，许多细菌似乎能够产生比已确定的更多的化合物。这些隐匿的化合物可能是有效的药物或具有其他重要的生物学功能。这使得鉴定这些途径和相关化合物成为一个重要的研究目标。然而，我们假设现有的基因组挖掘方法遗漏了许多重要的途径。在这个项目中，我们将结合使用计算、遗传和化学方法来识别这些分子，了解它们是如何形成的，并分析它们对临床和农业上重要病原体的生物活性。我们将专注于发现一类天然产物的新成员，称为核糖体合成和翻译后修饰肽（RiPPs）。从细菌到猴子，这些蛋白质都是在自然界中制造的，它们使用的是制造大蛋白的相同生物机制。然而，RiPP途径已经进化到制造更小的具有强大生物活性的天然产物。RiPP包括硫链酮，在兽医学中用作治疗细菌感染的抗生素，nisin，一种具有广谱抗菌活性的肽，用于食品加工以抑制细菌生长，以及齐iconotide，从锥螺RiPP中提取，用于治疗人类慢性疼痛。

Bacteria make an incredible number of chemical compounds that are invaluable for a variety of medical and agricultural purposes, including antibiotics, antifungals, anticancer compounds and insecticides. In fact, the majority of clinically used antibiotics come from soil-dwelling bacteria. This ability to produce these biologically active natural products stems from the evolutionary advantage the molecules provide to the producer. For example, bacteria have evolved the ability to produce powerful antibiotics to kill competing neighbouring microbes. The recent crisis in the rise of multi-drug resistant bacterial infections means that there is a pressing need to discover new antibiotics. We believe that there are many novel antibiotics that remain to be discovered from bacteria, but existing discovery methods are missing many hidden molecules that we call "metabolic dark matter".These natural products are produced by the action of a series of enzymes (proteins), which are encoded by genes (DNA) in the bacterial genome. Hundreds of thousands of bacterial genomes have now been sequenced. Researchers have developed methods to predict what compounds a bacterium should be able to make based on this genomic data ("genome mining"). This has revealed that many bacteria appear to be capable of producing many more compounds than have been identified. These cryptic compounds may be potent medicines or have other important biological functions. This makes the identification of these pathways and the associated compounds an important research goal. However, we hypothesise that many important pathways are missed by existing genome mining methods. In this project, we will use a combination of computational, genetic and chemical methods to identify these molecules, understand how they are made and analyse them for biological activity towards clinically and agriculturally important pathogens. We will focus on discovering new members of a class of natural product called ribosomally synthesised and post-translationally modified peptides (RiPPs). These are made across nature, from bacteria to monkeys, using the same biological machinery that makes large proteins. However, RiPP pathways have evolved to make much smaller natural products that have potent bioactivity. RiPPs include thiostrepton, which is used as an antibiotic to treat bacterial infections in veterinary medicine, nisin, a peptide with broad spectrum antibacterial activity that is used in food processing to suppress bacterial growth, and ziconotide, which is derived from a cone snail RiPP and is used to treat chronic pain in humans.