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

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.