Throughout 2016 Max and his collaborators, from the Max Planck Institute for Medical Research, have used published molecular structures of antibiotic resistant golden staph (Staphylococcus aureus), to see how we might overcome the resistance with new super-antibiotics.
Max tells us that in most situations golden staph is harmless; it lives on the skin and in the nose. “If, however, it enters the body it can cause a range of mild to severe infections – it can even cause death,” he warns.
Structural work done on golden staph at the Alfred, shows that in antibiotic resistant staph the cell walls of the bacteria are thicker, and so, regular antibiotics fail to penetrate this wall to reach where they need to, to be lethal. Max and his team want to work out how to recreate and optimise antibiotics in the lab so they pack a bigger punch when faced with resistant staph.
Something you might not know about antibiotics is that they are almost exclusively naturally occurring; they are grown by fermentation in thousand litre tanks and researchers then extract the antibiotics. However, to synthesise such antibiotics in a lab is rather difficult. Max and his team are looking at novel ways to synthesise (that is, grow) their own antibiotics. This way, they can engineer them to behave in specific ways, with the aim to have stronger, more efficient antibiotics to break through thick cell walls.
Because the team know, chemically, the end game — what the peptide antibiotic needs to ‘look’ like to be effective — their job is to work out how to manipulate connections between particular molecules so that they have the shape and the function they need.
An easy feat, this is not. But Max says that he and his group have made tremendous progress over the year. And, they only have one step to go!
“We all know that shape and function are intrinsically linked,” Max says. “By having control over the shape we can control the function. There are quite a few different steps involved in doing this though. And, depending on the order of the steps, we get differing results.”
“To link or fold the peptides we add enzymes, but how we add them, which ones will work and when we add them makes quite a difference. We’ve had success when we add two enzymes first and then add the third one. This gets us three quarters of the way to the final shape we want. And, to be clear, this shape is provided by the extra rings, and the rings are made by adding enzymes.”
By adding enzymes we force the peptides to join in particular orientations. Currently it isn’t possible to control all aspects of the natural compounds we use for fighting bacteria and infections. The key part of molecule, in terms of the function and the part that does the killing and binding, are very difficult to manipulate and change. They are also impossible to make on a commercially viable basis.
“Modifying what is on the outside can make a big difference to the function of the antibiotics, but if we can make them fold in the right ways then we have more control over the core of the antibiotics,” Max explained.
“When we have successfully made all four rings, meaning we have folded the molecule into the shape we want, we can test our antibiotics. We do this by letting the staph bacteria grow and then adding in our new antibiotic and watching how it is either killed or the growth of it is inhibited,” Max concluded.
Max and his team will continue working on the final step.
“We are close, but not quite there yet. Watch this space though, I think 2017 might be the magic year.
Max is an AI on the Imaging CoE, an EMBL group leader and a researcher in the Monash Biomedicine Discovery Institute.
Monash Biomedicine Discovery Institute
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 120 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.
