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 the University of Queensland in 2006, he moved to the Max Planck Institute for Medical Research in Heidelberg as a Cross Disciplinary Fellow of the Human Frontiers Science Program. He was subsequently awarded funding from the German Research Foundation (Deutsche Forschungsgemeinschaft) to establish his own group to investigate glycopeptide antibiotic biosynthesis as part of the Emmy Noether program. His group works at the boundary of chemistry and biology, where they apply a multidisciplinary approach including synthetic chemistry, biochemistry, structural biology and enzyme catalysis. In 2016, he joined EMBL Australia to continue his research into understanding the biosynthesis of important natural antibiotics and developing new antimicrobial agents. His group has made a number of important breakthroughs in understanding how nature synthesises the glycopeptide antibiotics, which are clinically relevant and synthetically complex molecules. For this work, he was awarded the 2016 Otto Schmeil prize by the Heidelberg Academy of Arts and Sciences. Currently, his group is investigating the biosynthesis of several important antibiotics as well as investigating novel strategies and targets for antimicrobial development.
The glycopeptide antibiotics (GPAs) are a structurally complex and medically important class of peptide natural products that include the clinical antibiotics vancomycin and teicoplanin. They contain a large number of non-proteinogenic amino acids and are produced by a linear non-ribosomal peptide synthetase (NRPS) machinery comprising seven modules. Furthermore, GPAs are extensively crosslinked late in their biosynthesis on the NRPS assembly line by the actions of a cascade of Cytochrome P450 enzymes, a process which contributes to the rigidity and structural complexity of these compounds. Due to the challenge of synthesising GPAs, biosynthesis remains the only means of accessing GPAs for clinical use, which makes understanding the biosynthesis of GPAs of key importance.
In this presentation, I will detail results from our studies into the NRPS machinery, the P450-catalysed cyclisation cascade and the interplay of these two important biosynthetic processes during GPA biosynthesis. This includes the characterisation of key enzymatic processes during NRPS-mediated peptide biosynthesis (chlorination, thioesterase activity and reconstitution of peptide synthesis) as well as the P450-mediated cyclisation cascade (substrate specificity of P450 enzymes and cascade reconstitution) from a number of different GPA biosynthesis pathways. Overall, our results demonstrate how selectivity during GPA biosynthesis is mediated through the careful orchestration of critical modification steps and interactions between the peptide-producing NRPS machinery and trans-modifying enzymes.