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Life just got more difficult for those fighting antibiotic-resistant superbugs. Researchers at McGill University have discovered two enzymes that use a never-before-seen mechanism to confer resistance, opening a whole new front in the battle against antimicrobial resistance (AMR), one of the top 10 global public health issues.

Albert Berghuis, a professor at McGill University, and Mark Hemmings, a Ph.D. student in his lab, were studying the types of enzymes that cause antibiotic resistance when they saw a structure that no one had ever seen before. Many resistance enzymes work by mimicking the antibiotic's target inside the bacterial cell, intercepting and deactivating the drug before it can do its job.

But they found two enzymes that attack aminoglycoside antibiotics without using this target-mimicry approach. Aminoglycosides are a class of broad-spectrum antibiotics used to treat severe bacterial infections.

"We found two enzymes that don't mimic the target at all," says Berghuis. "So, we wondered, are these still superbugs?"

The researchers used the Canadian Light Source at the University of Saskatchewan to examine the molecular structure of the enzymes and the drugs they bind to. They saw that the enzymes—called AAC(3)-Ia and AAC(3)-XIa—bind to the drug when its central ring structure is twisted into a pretzel shape rather than its usual flat disk.

This didn't seem like a particularly effective mechanism for resistance. Aminoglycoside molecules only spend about 0.1% of their time in the pretzel shape, says Berghuis, which doesn't leave many opportunities for the enzymes to grab and deactivate them.

"We didn't expect them to be very good enzymes," says Hemmings, but the results were a surprise: AAC(3)-XIa seriously outperformed their expectations. "One of them was pretty bad, but the other is actually just as good as the ones that do target mimicry." The researchers say more research is required to determine how the enzyme can be effective when it's so rarely in "attack" mode. The team's findings are in the journal Communications Chemistry.

Berghuis says the work should help in the fight against antibiotic resistance, by highlighting the fact that there are more kinds of enzymes that can cause resistance than we thought. Researchers will need to take these unconventional enzymes more seriously when they are identified in the genomes of bacteria.

"Before, we would have ignored enzymes like this, but now we have to take them into account," he says. "The problem (of antibiotic resistance) has grown and made life more complicated."