Incorporating altered substrates in GPA biosynthesis

Lead Chief Investigators: Max Cryle and Greg Challis, Monash University 

Collaborating Chief Investigators: Colin Jackson, Lara Malins, Gottfried Otting, Richard Payne



Nonribosomal peptides, including glycopeptide antibiotics (GPAs) are important for control bacterial infections in the clinic. Bacterial resistance is a growing threat to the use of GPAs; this occurs through altered H-bonding interactions with the GPA peptide backbone. Whilst efforts to redesign GPAs via synthesis have been effective, delivering new GPAs has stalled due limitations in the natural biosynthesis machinery for their production. Here, we will explore the incorporation of different building blocks into GPAs to produce designer GPAs that can overcome current resistance mechanisms.


Relevance to the Centre 

GPAs – exemplified by vancomycin – demonstrate the importance of peptide natural products for human health. Our ability to generate new compounds in this class is crucial to overcoming increasing bacterial resistance, yet we are unable to produce such molecules due to our reliance on biosynthesis for their production. This project will explore a novel strategy to alter nonribosomal peptides by the incorporation of designer peptide building blocks. In doing so, this will generate new GPAs and further explore the use of substrate mimetics as a general approach for the redesign of nonribosomal peptide synthetases across the broad range of compounds that we exploit in industry, medicine, and agriculture.