Taking on the superbugs

Five questions for Andrea O’Connor, Chemical Engineer.

Antibiotic resistance is fast emerging as one of the world’s most pressing medical challenges, with drug-resistant infections threatening to hinder simple procedures we currently take for granted – basic surgeries, medical device implants or intensive care. Associate Professor Andrea O’Connor (BE(Hons) 1990, PhD 1995) is at the forefront of the battle to beat the ‘superbugs’, pioneering the use of nanoparticles to fight infections at their source.

Dr Andrea O’Connor

Dr Andrea O’Connor is Deputy Head of the School of Chemical and Biomedical Engineering. Her expertise is in the field of biomaterials, implants and tissue engineering (the practice of merging scaffolds – tiny, porous devices that act as a template to regenerate tissue and organs – with human cells to repair wounds and damaged tissues)

1. What exactly is the problem you are trying to solve?

Conventionally, bacterial infections have been treated with antibiotics, but we are seeing lots of reports from the World Health Organisation and in the media about bacteria developing resistance. So, we’re interested in finding alternatives to antibiotics, particularly in the areas where we are doing research, which are medical devices – hip implants, valves for hearts, plates and screws… things mostly made of metals and plastics, sometimes from ceramics – and in the field of tissue engineering. With the latter, we try to make materials, sometimes like a sponge, that you might put into the body to repair tissue, or replace tissue that is missing, after people have maybe had a car accident or major trauma, surgery due to cancer, something like that.

As bacteria are becoming more drug resistant, it’s harder and harder to treat those things. It’s already difficult, because bacteria are very good at evading the immune system, and when they sit on the surface of something like an implant they can grow a biofilm, which is like a gooey layer, that protects them and which makes it tough for the antibiotics to get in to treat the bacteria. The bacteria become what we call quiescent; they sort of slow down, and just exist there, though they’re not very active.

From the perspective of medical devices, these kinds of infections can be a major problem. If an implant becomes infected, it may fail, and that can lead to major problems for the patient.

2. What’s so good about nanoparticles?

Nanoparticles are very small particles – typically, below 100 nanometres in size, and a nanometre is one-billionth of a metre. But nanoparticles are attractive for a few reasons; interestingly, they have a lot of surface area relative to the total amount of material. Because they’re microscopic, a lot of the actual particle is surface as opposed to mass, and that displays different chemical activity compared to a large block of the same material. That means there is a lot of surface area for things to interact with, and one of the things that that changes, is how the particles might interact with cells and bacteria, and how quickly they might dissolve or undergo chemical reactions, because a lot of those things happen at the surface of the particle, not inside the particle.

It has been shown that nanoparticles of some materials, like silver, are quite good at killing bacteria, and so silver has been used for decades for that purpose, and it’s now incorporated in some wound dressings, band aids, even some clothing. But silver is also toxic, so it’s not ideal, and for that reason we’ve looked at other materials.

We did some work with other nanomaterials that had interesting interactions with cells, like zinc oxide and titanium oxide, and some of these will increase the growth of human cells on a surface, for example. But none of the ones we originally tested were as effective against bacteria as the silver had been.

3. Selenium, the silver bullet?

A post-doctoral researcher in my lab, Dr Phong Tran, who’s now at Queensland University of Technology, had some experience in working with selenium as a material that had antimicrobial properties. So we started investigating that, and that has led to collaboration with Professor Neil O’Brien-Simpson’s team in the Melbourne Dental School and some exciting results that look really promising.

Selenium looks to be somewhat in the sweet spot in that it is quite effective against bacteria, but it’s much less toxic to human cells. It’s actually an important dietary element; we need a small amount of selenium, a tiny amount, in our diets, and it forms complexes with proteins in the body and helps with some of our immune function.

So, it’s much safer. It means you can use more of it, and it’s very effective against a class of bacteria we call Gram-positive bacteria, a common example of which is Staph aureus – Staphylococcus aureus, or Golden Staph – which has drug-resistant variants that are in the Australian community and hospitals and can cause significant problems. We’ve been able to control the properties of the selenium nanomaterials now, by synthesising them carefully in different ways, so that we can attack those drug-resistant forms of the Gram-positive bacteria, as well as the normal forms of bacteria.

And then we made another step in the synthesis that we’re aiming to take out a patent on, where we can actually produce selenium-based nanoparticles that will also attack Gram-negative bacteria, which are typically more difficult to attack. That’s things like E. Coli, which is also quite prevalent and causes a lot of illness.

One of the things that bacteria need to stay functioning is their cell membrane. If it starts to get holes in it or starts to leak, then the bacteria don’t function well and if it gets bad enough then they will die.

One of the ways that these nanoparticles can attack bacteria is by disrupting that membrane so they make the bacteria leaky, and then things can pass in and out of the bacteria in a way they normally wouldn’t.

In tests, we’ve incorporated the nanoparticles as a coating on the surface of a medical implant, or as part of a tissue-engineering scaffold. The antimicrobial components are then gradually released into their surrounding environment, and prevent infections forming.

Our research focus has been on medical devices, so that could be implants, it could also be things like catheters, where biofilm infections can be a problem. A lot of the devices used in surgery and in hospitals are prime sites for these kinds of infections.
Another major problem is wounds, chronic wounds, and particularly for patients who are elderly and who may have diabetes; they are very prone to ulcers and chronic wounds that don’t heal well, and those can often suffer from superbug-type infections.
So we’re producing wound dressings and wound regeneration scaffolds, that might incorporate these antimicrobial components. They would ideally help to heal the wound, while also preventing infection.
4. You mentioned developing a patent as part of this exploration. Where to from here?

We are working to better optimise and understand the performance of the nanoparticles that we’ve produced. We’re looking to do more biological testing of those. We’ve tested them against eight different kinds of bacteria, we’ve tested them with human cells, and we’re looking to do longer term biological testing to see how they perform over a long time. One of the key things about nanoparticles, is that we expect the bacteria won’t develop resistance to them as easily as they do to a lot of drugs, because the nanoparticles have multiple ways that they attack the bacteria.

So this is something that we’re really trying to understand – what aspect of a material means that bacteria can, or cannot, develop resistance readily? To understand that would really be a very big step forward. We’re part way down that track and we think we’ve got some exciting avenues to follow there.

That’s one aspect, and then we’re also working with a medical device company in Melbourne, and on our own development, to try and implement this type of technology, develop materials for wound dressings, and ways that we could use them in medical devices.
We’re not the only people who ever thought of using nanoparticles, so we’re building on previous work and other researchers have investigated selenium and seen that it has beneficial properties. But we think that there are some really exciting developments that we’re making – and we are aiming to make – that I think should make a difference. Ultimately, the most exciting thing would be if we could have this technology adopted in medical devices, so that it actually impacts peoples lives and makes a difference.

I think we need lots of strategies to do that given the rise of superbugs. No one strategy is going to be the solution to everything, but this could be a part of it, which is very exciting.

5. How many superbugs have been identified? Are we talking hundreds? Thousands?

There’s a set that have been identified called the ESKAPE pathogens, which are a handful of pathogens that are known to be prone to drug resistance. But there are many different strains. The other thing that I’ve been really struck by as we work with human and mammalian cells, is that when we switch to growing bacteria and testing them, they grow so fast, and they replicate and they change so fast. It’s quite shocking when you’re used to dealing with mammalian cells that chug along and double once a day, sort of thing. These bacteria have been through several generations in that time, so the challenge that superbugs present is really quite striking.