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Pacidamycin: an unusual antibiotic with a curious biogenesis. Unravelling the intriguing construction of the peptide backbone.

帕西达霉素：一种不寻常的抗生素，具有奇特的生物起源。

基本信息

批准号：
BB/I022910/1
负责人：
Rebecca Goss
金额：
$ 49.25万
依托单位：
University of East Anglia
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2011
资助国家：
英国
起止时间：
2011 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FI022910%2F1
关键词：
Pacidamycin unusual antibiotic curious biogenesis.

项目摘要

The majority of medicines in the clinic are based on natural products with a considerable proportion of these being assembled by multifunctional enzyme assembly lines; this can be paralleled with automobile assembly lines with different sections of the enzyme responsible for introducing each component of the natural product. Pacidamycin is an antibiotic with a clinically unexploited mode of action and good selective activity against Pseudomonas aeruginosa, a problem pathogen for burns patients and cystic fibrosis sufferers in particular. We have demonstrated that this structurally unusual natural product is generated by an intriguing nonribosomal peptide synthetase assembly line. Investigations into the construction of this structurally unusual antibiotic are likely to provide fundamental insights as to how different sections of multifunctional enzymatic assembly lines communicate and interact. Understanding the molecular machinery will enable us to harness this and other antibiotic factories in order to enable expeditious access to new designer natural products. Our investigations will also inform on the assembly of two unusual amino acids that are components of pacidamycin. Diaminobutyric acid is a component of a number of biologically important natural products, and whilst sixteen chemical syntheses of this compound have been reported, little is known about its natural assembly. We will determine whether the biogenesis might be tamed in order to enable a biological one-step synthesis of this amino acid and its analogues. The meta-tyrosine residue is also highly unusual and we will carry out investigations into its assembly.

临床上的大多数药物都是基于天然产品，其中相当大一部分是由多功能酶组装线组装的;这可以与汽车组装线相结合，其中酶的不同部分负责引入天然产品的每种成分。Pacidamycin是一种抗生素，具有临床上未开发的作用模式和对铜绿假单胞菌的良好选择性活性，铜绿假单胞菌是烧伤患者和囊性纤维化患者的问题病原体。我们已经证明，这种结构不寻常的天然产物是由一个有趣的非核糖体肽合成酶装配线。对这种结构上不寻常的抗生素的构建的调查可能会提供关于多功能酶组装线的不同部分如何通信和相互作用的基本见解。了解分子机制将使我们能够利用这种和其他抗生素工厂，以便能够迅速获得新的设计师天然产品。我们的研究也将告知两个不寻常的氨基酸，是紫杉霉素的组成部分组装。二氨基丁酸是许多生物学上重要的天然产物的组成部分，虽然已经报道了这种化合物的16种化学合成，但对其天然组装知之甚少。我们将确定生物起源是否可以被驯服，以便能够生物一步合成这种氨基酸及其类似物。间酪氨酸残基也是非常不寻常的，我们将对其组装进行调查。