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MASSIVE Research Stories: Making Sense of Drug Resistance in Pathogenic Bacteria

Around the world researchers are striving to find new ways to treat infections as antibiotics lose their ability to halt the spread of pathogenic bacteria.

Over time, the so-called 'superbugs' have developed resistance to the latest and until now the best antibiotics. Clearly, new approaches are needed to understand the process of antibiotic resistance and to design better drugs and treatments.

Monash researchers are making a major contribution to the push to eliminate superbugs. Among them, Dr Matt Belousoff, working together with Professor Trevor Lithgow, spends much of his time looking very closely at the structure of bacterial ribosomes, the molecular machines that make proteins and enable the bacteria to thrive.

He wants to find out how the structure changes when infectious bacteria undergo mutation that leads to drug resistance.

Most antibiotics target a specific aspect of cellular metabolism. Penicillin for example targets the bacterial cell wall. But under constant exposure to the antibiotic, the occasional bacterial cell can mutate to survive treatment and start a new drug-resistant strain.

To try and answer the question of why antibiotics stop working, Belousoff uses advanced imaging techniques to visualise changes in ribosomes that occur in response to certain antibiotics.

He and his colleagues have their sights set on the design of new drugs that are lethal to bacteria despite structural changes to ribosomes - a 'super drugs for super bugs' scenario.

Even though Belousoff is not even sure where the MASSIVE computers are housed, he affirms that MASSIVE plays a central role in moving his research along.

As he puts it, most of his time is spent "staring at a UNIX terminal in my lab and typing commands". His main interaction with MASSIVE is at the human level.

"The software engineers from MASSIVE are really helpful and knowledgeable when I need to get new software up and running," he said.

"The software we use is all open source, which is a plus. But the down side is that nothing works first shot. The published code can need quite a lot of editing before it will do just what I want."

Ready access to MASSIVE's computer cluster is also critical. Matt takes high resolution images (about 500,000 at the movie-frame rate) of pure preparations of ribosomes isolated from hospital-acquired antibiotic-resistant Staphylococcus aureus.

His images take a huge amount of storage and processing, which, without MASSIVE, would be prohibitively expensive. And supercomputing through MASSIVE makes sense of all the images by transforming a 3-D electron density map into a meaningful molecular model that he can work with.

"The knowledge gained about the effects of mutations that lead to drug-resistance on the ribosome binding site will help us to re-engineer the binding site in the future. It's an exciting idea from the perspective of drug-development, and could lead to one drug for the treatment of all antibiotic-resistant strains," Belousoff said.

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Figure 1: One of Dr Matt Belousoff and Professor Trevor Lithgow ribosome structures illustrating the complicated details that can be determined using the Titan Krios at the Ramaciotti Centre for Cryo Electron Microscopy and MASSIVE.

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