Chemo-bioengineering methods for cost-effective production of the antibiotic argyrin and its analogues

One of the major global challenges in modern medicine is the unprecedented rate of increase in antimicrobial resistance in bacteria to all known classes of antibiotics. In this context, using cutting-edge synthetic chemistry, we have discovered new argyrin analogues (Org. Biomol. Chem. (2014), 12, 9764) with good antimicrobial activity. However, the chemical methods used for the manufacture of argyrin analogues are both time-consuming and costly.
Since the argyrins are natural cyclic peptides produced by myxobacteria and actinomycetes, this project will focus on the development of novel chemo-bioengineering methods for cost-effective large-scale production of argyrin analogues. The naturally occurring argyrin A is a 24-membered cyclic peptide comprised of several unique amino acid residues, including 4-methoxytryptophan, dehydroalanine and a thiazole dipeptide. The latter two residues are known to be derived via dehydratase-mediated dehydration of a serine residue and dehydrative cyclisation of cysteine-containing dipeptides, respectively. Thus, using known argyrin A-producing organisms, we will use conventional microbial genetics, next generation sequencing and genome mining to identify the argyrin biosynthetic gene cluster and in particular the dehydratase and cyclo-dehydratase genes and gene products. Ultimately, we will determine if novel amino acid analogues could be utilised as substrates for the bioproduction of argyrin analogues. This project will provide training in modern experimental techniques in chemical and synthetic biology.