Understanding Glycopeptide Antibiotic biosynthesis – a pathway to developing new antimicrobial agents?

A/Prof. Max Cryle
EMBL Australia Group Leader
Department of Biochemistry
Monash Biomedicine Discovery Institute

Abstract: Non-ribosomal peptide synthesis is a vital source of many important natural products, including compounds with anticancer, antibiotic, antifungal and immunosuppressive activities. By removing the constraints imposed by ribosome-based synthesis, non-ribosomal peptide synthesis can exploit a range of monomers far greater than standard proteinogenic amino acids: to date, more than 500 different monomers have been identified and these, combined with many further modifications, can have dramatic effects on the structural and biological diversity of these compounds. The enzymatic machinery that produces these compounds is a group of fascinating megaenzyme synthases known as non-ribosomal peptide synthetases (NRPSs). Utilising a modular architecture of repeating catalytic domains and combined with multiple interaction partners in trans, NRPSs have long been recognised as potential targets for enzymatic redesign to produce new, bioactive compounds. To date, this research has largely been hindered by a lack of understanding of how NRPSs function: my group aims to overcome these limitations by focusing on the characterisation of specific, important examples of NRPS biosynthesis. In this presentation I will showcase the results of our research glycopeptide antibiotic biosynthesis – with particular reference to halogenation and the peptide cyclisation cascade – and show how an interdisciplinary approach combining chemistry, biochemistry and structural biology is needed to fully understand these complex biosynthetic systems.

Bio: A/Prof. Max Cryle is an NHMRC Career Development Fellow and EMBL Australia Group leader based in the Biomedicine Discovery Institute at Monash University. After obtaining his PhD in chemistry from UQ in 2006, he moved to the Max Planck Institute for Medical Research in Heidelberg as a HFSP Cross Disciplinary Fellow. He was subsequently awarded funding from the German Research Foundation to establish his own group to investigate glycopeptide antibiotic biosynthesis as part of the Emmy Noether program: for this work he was awarded the 2016 Otto Schmeil prize by the Heidelberg Academy of Arts and Sciences. In 2016 he joined EMBL Australia where his group investigates the biosynthesis of several important antibiotics and investigates novel strategies and targets for antimicrobial development.