Exploiting a novel peptide cyclase to make new antibiotics

利用新型肽环化酶来制造新抗生素

• 批准号: 2425803
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2425803
• 关键词: Exploiting; novel; peptide; cyclase; make

Without new antibiotics the global healthcare system will collapse. Many antibiotics originate from a class of microbial natural products called non-ribosomal peptides, the vast majority of which are cyclic. Cyclisation of these peptides is often inefficient so new approaches are sought after in this area. We recently identified a novel non-ribosomal peptide cyclase with considerable substrate promiscuity. If this promiscuity can be understood, then it can be harnessed for biotechnology to improve chemical synthesis of antibiotics and other high-value cyclic peptides.In this project you will purify the peptide cyclase and interrogate its substrate specificity in vitro. You will also pursue structural studies with the cyclase using X-ray crystallography and use the resulting structure to rationally re-engineer its substrate specificity. The activities pursued during the project are supported by World-class infrastructure and support within the Astbury Centre for Structural Molecular Biology. You will have an opportunity to learn a wide range of techniques including: protein purification, peptide synthesis, LC-MS, NMR, X-ray crystallography and many others. The outcomes of this project will have a direct impact on the AMR crisis by developing methodology for enhancing the synthesis of novel peptide antibiotics.

如果没有新的抗生素，全球医疗体系将崩溃。许多抗生素来源于一类称为非核糖体肽的微生物天然产物，其中绝大多数是环状的。这些肽的环化通常是低效的，因此在该领域寻求新的方法。我们最近发现了一种新的非核糖体肽环化酶，具有相当大的底物混杂。如果这种混杂性可以被理解，那么它就可以被用于生物技术，以改善抗生素和其他高价值环肽的化学合成。在这个项目中，你将纯化肽环化酶，并在体外研究其底物特异性。您还将使用X射线晶体学对环化酶进行结构研究，并使用所得结构合理地重新设计其底物特异性。该项目期间开展的活动得到了阿斯特伯里结构分子生物学中心世界级基础设施和支持的支持。您将有机会学习广泛的技术，包括：蛋白质纯化，肽合成，LC-MS，NMR，X射线晶体学等。该项目的成果将通过开发增强新型肽类抗生素合成的方法，对AMR危机产生直接影响。