Exploiting a novel peptide cyclase to make new antibiotics

如果没有新的抗生素，全球医疗体系将崩溃。许多抗生素来自一类被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。这些多肽的环化效率往往很低，因此在这一领域寻求新的方法。我们最近发现了一种新的非核糖体多肽环化酶，具有相当大的底物杂交性。如果可以理解这种混杂，那么它可以被生物技术利用来改进抗生素和其他高价值环肽的化学合成。在这个项目中，你将纯化多肽环化酶，并在体外询问它的底物专一性。您还将使用X射线结晶学对环化酶进行结构研究，并使用得到的结构合理地重新设计其底物专一性。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内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、多肽合成、LC-MS、核磁共振、X射线结晶学等。该项目的结果将通过开发加强新型多肽抗生素合成的方法学，对AMR危机产生直接影响。

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.