Fighting antibiotic resistance with axes…we mean proteins

The next weapon against antibiotic resistance might be sourced from within our own immune systems, according to a team of Australian researchers. Now that’s bioinspiration.

The researchers have shown that a class of proteins called guanylate-binding proteins (GBPs) can identify and destroy bacteria, as well as triggering the immune system to recognise them. These proteins could be used in concert with antibiotics to better destroy bacteria – or, one day, they could become their own treatments.

The research is published in Nature Communications.

“Our research initially was inspired by the immune system,” says co-author Professor Si Ming Man, a researcher at the Australian National University’s John Curtin School of Medical Research.

“We were looking at a type of immune cells called macrophages, which is like the defender of the body. And we found that when this type of immune cell gets attacked by bacteria, they produce a group of molecules, or proteins, that directly mark the bacteria inside the cell.”

These proteins are a double threat: they can destroy the bacteria, and they also trigger inflammation and other immune responses, so that our bodies can fight the infection off.

“The process of destroying the cell is pretty much like an axe hitting a melon,” explains Man.

“Normally your immune system can only look at the surface of a watermelon. But then, if you chop the watermelon open, and all the guts and contents spew out, now your immune system has a new opportunity to recognise all the aspects of the watermelon – which includes the seeds, the fruit, the sugar, and things like that.

“It presents everything to the immune system. We have a better ability to go and fight this infection because now we are able to pick up every single part of the bacteria and know what to fight.”

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The researchers have shown in mice that a couple of these guanylate-binding proteins are required for triggering inflammation and an immune response. They also synthesised the two proteins in a lab, showing that they could target and destroy two specific strains of bacteria, without damaging other cells.

“We believe we can extract and harness the power of these immune system proteins, known as GBP1, and use them to treat a range of infectious diseases, without negatively affecting our body’s cells,” says first author Shouya Feng, a PhD candidate also at ANU.

But given humans also have these proteins, they suspect the finding could go much further.

“Based on this observation from the lab, we thought: wouldn’t it be interesting to harness the power of these immune proteins, and then turn that into a drug?” says Man.

“Using this protein directly we can destroy a lot of different specific types of bacteria that cause disease, but also we identified the key part of these proteins – the sharp bits of the axes.”

By zooming in on the “killing” part of the protein, Man hopes they’ll be able to make smaller, and more effective, drugs. Proteins are typically made of hundreds to thousands of amino acids, joined together – but they don’t need to be so big to do their jobs.

“We can get down to like 11 amino acids, rather than like a giant protein which is very expensive to make,” says Man.

“By making a very small part of it, it’s much cheaper.”

Next, the researchers are hoping to see whether there are more GBPs that are similarly good at destroying bacteria.

“We know that this family is pretty big,” says Man.

“There could be potentially new unexplored proteins.”

They’re also investigating how to improve the stability and the potency of the proteins they have found.

“We’ve tested in animals and know that it is effective. [We hope] we can eventually take it further in human trials. That’s further down the line,” says Man.

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