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Scientists Make Important Discovery Around Antibiotic Resistance

Date: 
Wednesday, May 3, 2017

Researchers from McGill University have discovered why superbugs are resistant to certain antibiotics and are one step closer to finding new treatments.

“Superbugs have different tricks up their sleeves on how to resist antibiotics. We became interested in looking at how they resist these macrolide antibiotics, like erythromycin ,” said Dr. Albert Berghuis, chair of the Department of Biochemistry at McGill University’s Faculty of Medicine.

Macrolide antibiotics are the fourth largest class of antibiotics and are prescribed for a variety of infectious diseases, including upper respiratory tract, skin and soft tissue infections. Erythromycin and other macrolide antibiotics are also prescribed as an alternative to penicillin. In 2009, sales of macrolide antibiotics in the U.S. topped $4.8 billion.

Dr. Berghuis and his colleagues conducted research using the intensely bright light at the Canadian Light Source, the only synchrotron in Canada, and were able to analyze at the atomic level enzymes called kinases. The research group’s findings have just been published in the journal Structure.

Data resulting from shining the intense bright light of the CLS at samples of bacterial kinases with different macrolide antibiotics . The location and brightness of spots and where they are in the video allowed Dr. Berghuis' team to calculate the detailed atomic structure for the antibiotic resistance enzymes. Courtesy of Dr. Berghuis

It’s the enzymes in the bacteria that have the ability to chemically modify antibiotics. The enzymes take a molecule that has a phosphate group in it and they stick that phosphate group on to something else, explained Dr. Berghuis.

“In the kinases that we studied, they stick the phosphate group on to the macrolide antibiotic and that little change is just enough to make them no longer an antibiotic. When that happens, it becomes a useless compound and the bacteria lives happily ever after which is not good for us.”

Dr. Berghuis compared the process of an enzyme attacking an antibiotic to using a coloured marker. When the lid is not on the marker, the marker can be used to colour on paper covering whatever is on the paper, just as a macrolide antibiotic covers a bacteria and kills it. You put a lid on that marker and it can no longer be used to colour. Similarly, when the bacteria’s enzyme attaches a chemical to the antibiotic, it also is rendered useless.

The images and data collected at the Canadian Light Source provided the essential information in out-tricking superbugs.

“We now know in exquisite detail how these macrolides interact with the enzymes. That exquisite detail is critical if you want to make a version of these macrolides that don’t bind anymore to the enzymes. Without that information, this whole plan goes out the window. That’s what the CLS allowed us to do.”

Now that researchers know how this process works, the next step will take them back to the chemistry laboratory.

Left: An image of a bacterial kinase (in yellow) just before it renders a macrolide antibiotic (the black, white and red balls) useless. Right: Closeup of the bacterial kinase and how it recognizes a macrolide antibiotic. The net is derived from the data measured at the CLS, which allowed Dr. Berghuis and co-workers to determine in exquisite detail how the macrolide antibiotics precisely interacts. This information is critical for design new antibiotics that are resistant to the resistance. Courtesy of Dr. Berghuis

“With this knowledge, we can design a slightly different antibiotic that the enzymes can no longer recognize. We can make a variant of the macrolide that is resistant to the resistance.”

Dr. Berghuis estimates that the development of new macrolide antibiotics will take two to three years and then more time will be needed for clinical trials before they are readily available. In the meantime, he says everyone needs to do their part in the battle against superbugs by using antibiotics appropriately. Overuse and improper use, not completing medication, have contributed to development of superbugs and their antibiotic resistance.

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Fong, Desiree H., David L. Burk, Jonathan Blanchet, Amy Y. Yan, and Albert M. Berghuis. "Structural Basis for Kinase-Mediated Macrolide Antibiotic Resistance." Structure (2017). DOI: 10.1016/j.str.2017.03.007

Story by Lana Haight

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