Understanding the biosynthesis of peptide antibiotics by non-ribosomal peptide synthesis

Non-ribosomal peptide synthesis is a complex biosynthetic process that produces many medically important peptide natural products, including several classes of vital antibiotics such as the glycopeptide antibiotics. As many of the structures of these antibiotics are too complex to produce commercially via chemical synthesis, our ability to access these and related compounds for use in the clinic depends on natural biosynthesis. Thus, gaining an understanding of the enzymatic machineries that make these complex antibiotics in vivo is vital for our ability to generate new compounds to continue the fight against resistant bacterial infections. This project seeks to understand the non-ribosomal peptide synthesise machinery that is central to the synthesis of these antibiotics through a series of biochemical and structural investigations of this modular peptide assembly line. The project will combine protein expression and purification, enzymology, analysing protein-protein interactions and biochemistry together with structural biology techniques such as X-ray crystallography and cryo electron microscopy (Cryo-EM).