Developing chemoenzymatic approaches to generate new peptide antibiotics

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 combine the impressive power of biosynthetic enzymes with the ability of synthetic peptide chemistry to rapidly generate multiple diverse peptide substrates in vitro to enable structure/activity relationships of novel peptide antibiotics to be explored. The project will combine chemical synthesis, enzymology, protein chemistry as well as biocatalysis and biochemistry.