September 15, 2016

Max Cryle talks: molecular machines

Max Cryle wears a few hats: he is an AI on the Imaging CoE, an EMBL group leader and a researcher in the Monash Biomedicine Discovery Institute. He wore all his hats at once and spoke to us about his recent review. Watch the video, read the interview or live on the wild side – do both!

Claiming the lives of an estimated 700,000 people each year – and predicted to kill 10 million people a year by 2050* – drug-resistant superbugs are a major threat to public health worldwide. Antimicrobial resistance happens when bacteria, viruses, parasites, and fungi become resistant to medicines that were previously able to treat them. With only two new classes of antibiotics discovered since the 1960s, the race is on to discover new medicines, or redesign old ones, to fight these superbugs.

Associate Professor Max Cryle’s work focuses on uncovering ways to redesign the drugs we currently have, or creating new ones, to destroy these antimicrobial resistant superbugs.Max said many of the drugs used in the clinic were produced by the natural machinery in bacteria, and couldn’t be mass-produced any other way.

“That’s because these drugs are made up of very complex molecules, and the natural machineries in bacteria that make them do it very well,” Max said.

“But the disadvantage of producing drugs this way, is that it makes it hard to change the structure of them and change the way they act. If we want to do that, then we need to understand exactly how the bacteria’s machinery works, and from there we can do some effective drug redesign.”

Associate Professor Cryle recently led a review published in the journal Angewandte Chemie, to help understand how a diverse family of natural products, called nonribosomal peptides, are made.  These natural products are made by bacteria, and are the basis of many antibiotic, antifungal, and anticancer drugs. Associate Professor Cryle said the majority of the bacterial machinery that produced these key drugs was poorly understood.

“Trying to redesign these drugs without first understanding how the machinery works is like walking off the street into a factory that makes cars and trying to make a new model – you can change things easily enough, but more than likely you’ll just break the production line.”

In this latest review, the research team focused on a small protein that is the traffic controller of the production line, peptidyl carrier protein. The movement of this protein determines the eventual drug that is produced, but how the protein knows where to travel has been poorly understood. Associate Professor Cryle now has a theory to test about how the protein moves.

“It turns out to be a mixture of a very controlled process where the protein is physically moved, as well as a more random enzyme reaction process,” Max said.

“Now we can test our theory in future experiments. Once we understand this machinery better, we can work to control the process more, which will help us to design new drugs.”

New Structural Data Reveal the Motion of Carrier Proteins in Nonribosomal Peptide Synthesis
http://onlinelibrary.wiley.com/doi/10.1002/anie.201602614/full

Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 100 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.