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

Lead Research Organisation: University of Nottingham
Department Name: Sch of Pharmacy

Abstract

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.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M008770/1 01/10/2015 30/09/2023
1647898 Studentship BB/M008770/1 01/10/2015 30/09/2019 Francesco Tarantini
 
Description As part of this work, a novel bacterial specimen has been characterized and named Actinomadura graeca. The latter was also confirmed as a novel producer of the peptide macrocyclic antibiotic zelkovamycin and the putative genes responsible for its biosynthesis have been identified.

The antibacterial properties of zelkovamycin have been investigated, and the antibiotic was found to be active against selected Gram-positive and Gram-negative bacteria. Lastly, the target of zelkovamycin in Staphylococcus aureus has been elucidated.
Exploitation Route Knowledge of the biosynthetic genes for zelkovamycin will facilitate their characterization and exploitation for the biological production of zelkovamycin analogs. At the same time, knowing the molecular target of zelkovamycin and understanding its interaction with the antibiotic will guide rational modifications aimed at improving the biological activity of the drug.
Sectors Pharmaceuticals and Medical Biotechnology