Evolution-inspired engineering of non-ribosomal peptide synthetase assembly lines to create novel bioactive scaffolds

受进化启发的非核糖体肽合成酶装配线工程，以创建新型生物活性支架

• 批准号: BB/X010619/1
• 负责人: Alex Mullins
• 金额: $ 47.46万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX010619%2F1
• 关键词: Evolution; inspired; engineering; non; ribosomal

Microorganisms and plants supply the world with a considerable number of bioactive compounds used in medicine and agriculture. Small changes in the structure of these compounds can influence their efficacy as antibiotics and anti-cancer agents (used in hospitals to treat serious diseases), and pesticides (used in agriculture to protect crops).Many of these biologically active compounds are produced in bacteria by large multi-enzyme systems known as non-ribosomal peptide synthetases (NRPSs), that work as an assembly line to create the final product. These assembly lines are encoded in bacterial genomes by sets of genes known as biosynthetic gene clusters (BGCs). By removing, duplicating, or substituting different sections of the BGCs encoding these assembly lines, bacteria can modify the final product.My project aims to exploit publicly available bacterial genome sequence data to identify natural examples of these BGC variations in Pseudomonas bacteria using bioinformatics techniques and catalogue these variants. We can use this data to see the exact positions employed by Nature to modify the BGCs and apply these rules to make novel alterations while not disrupting the overall function of the assembly line. The BGC responsible for making the natural product called orfamide A will be captured and subsequently modified through the removal, duplication, or substitution of different sections. Initially, I will re-create examples of known BGCs to trial the modification strategy, but I will later apply this technique to create novel BGC variants and new natural products. This synthetic biology approach to creating BGC variants will bypass the need to acquire bacterial strains from difficult to access sources and lead to the creation of novel scaffolds. The natural product variants resulting from this approach will be tested for antimicrobial, anti-cancer, and biopesticidal properties.The outcomes of this project will accelerate the rational design and bioengineering of NRPS systems enabling novel compounds with beneficial properties for clinical, industrial, and agricultural to be created.

微生物和植物为世界提供了大量用于医学和农业中使用的生物活性化合物。 Small changes in the structure of these compounds can influence their efficacy as antibiotics and anti-cancer agents (used in hospitals to treat serious diseases), and pesticides (used in agriculture to protect crops).Many of these biologically active compounds are produced in bacteria by large multi-enzyme systems known as non-ribosomal peptide synthetases (NRPSs), that work as an assembly line to create最终产品。这些组装系通过称为生物合成基因簇（BGC）的基因组编码在细菌基因组中。通过删除，复制或替换编码这些组装线的BGC的不同部分，细菌可以修改最终产品。我的项目旨在利用BGC的自然示例来利用这些BGC变化的自然示例，使用BGC变化，使用BioInformitictics和Catalog catalog catalsog catalog catalog catalog catalog catalog catalog catalog catalog catalog catalog catalog catalog catalog。我们可以使用这些数据来查看自然所使用的确切位置来修改BGC并应用这些规则以进行新的更改，同时又不破坏装配线的整体功能。负责制造称为Orfamide A的天然产品的BGC将被捕获并随后通过删除，重复或替换不同部分进行修改。最初，我将重新创建已知BGC的示例以试用修改策略，但后来我将应用此技术来创建新型的BGC变体和新的天然产品。这种创建BGC变体的合成生物学方法将绕开从难以进入来源获取细菌菌株并导致创建新型脚手架的必要性。该方法产生的自然产品变体将测试用于抗菌，抗癌和生物农药特性。该项目的结果将加速NRPS系统的合理设计和生物工程，从而实现具有临床，工业，工业和农业的有益特性的新型化合物。