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

临床上的大多数药物都是以天然产品为基础的，其中相当大一部分是由多功能酶装配线组装的；这可以与汽车装配线并行，汽车装配线的不同部分的酶负责引入天然产品的每个成分。帕西霉素是一种临床上尚未开发的抗生素，对铜绿假单胞菌具有良好的选择性活性，铜绿假单胞菌是烧伤患者特别是囊性纤维化患者的问题病原体。我们已经证明了这种结构上不寻常的天然产物是由一条耐人寻味的非核糖体肽合成酶装配线产生的。对这种结构上不寻常的抗生素结构的研究可能会为多功能酶装配线的不同部分如何沟通和相互作用提供基本的见解。了解分子机制将使我们能够利用这个和其他抗生素工厂，以便能够快速获得新的设计天然产品。我们的研究还将揭示两种不寻常的氨基酸的组装情况，这两种氨基酸是帕西霉素的组成部分。二氨基丁酸是许多具有重要生物意义的天然产物的组成部分，虽然已经报道了该化合物的16种化学合成方法，但对其自然组装情况知之甚少。我们将确定是否可以驯服生物发生，以实现这种氨基酸及其类似物的生物一步合成。偏酪氨酸残基也非常不寻常，我们将对其组装进行调查。

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.