On the warpath

Melissa Brown has been fighting a cunning enemy for decades in a war that never ends and has the potential to drive human health outcomes back to Victorian times.

“Bacteria are clever little things, I tell you; it doesn't matter what you throw at them, they can fight it somehow or other,” the Professor of Microbiology at Flinders University says.

While the search intensifies to find new antibiotics to overcome the increasing threat of multi-drug resistant microbes, Professor Brown is taking a different approach, trying to block the bacteria’s ability to resist in the first place.

“It’s got to be a multi-pronged approach and the search for new drugs is important,” she says. “But finding new antimicrobials is the hard thing to do because the bacteria have already got their whole repertoire of mechanisms that they can use to combat these things we throw at them. It's very rare to find something brand new and novel, so everybody modifies old ones and that's fine for a while, but if the bacteria have already got the mechanism to resist the progenitor of it, then they're going to be able to resist that one as well at some stage.”

For the past 30 years or so, Professor Brown has been focusing on one bacteria in particular –Staphylococcus aureus, known to most of us as Golden Staph. While common, and harmless in most circumstances, it is not to be underestimated. If it enters the body through a cut it can cause potentially deadly infections. Before antibiotics, it was fatal in 80% of infected wounds.

To add to the risk it is easily spread by skin-to-skin contact, or by touching contaminated surfaces. It is particularly prevalent in hospitals and increasingly resistant, not just to antibiotics but to antiseptics and disinfectants.

It is little surprise then that these latter compounds are a major concern of Professor Brown’s research. 

“We're trying to stop the spread in the hospitals, on handrails or bed rails or on the sheets, because these bacteria then resist all of those control measures,” she says.

COVID had a terrible impact on the problem with a more indiscriminate use of antibiotics, antiseptics and disinfectants. “People were going to hospital with COVID and getting bacterial infections. Doctors didn't have time to work out what infection it was and were just throwing antibiotics at people. And then we were using everything we could to sanitise our hands, which was necessary of course but was also selecting for bacteria that are resistant to those handwashes as well,” Professor Brown says.

She and her team have identified what they hope is Golden Staph’s Achilles heel, its “multi-drug efflux pump”, a protein that sits in the bacterium’s outer shell and acts as a vacuum cleaner, expelling antimicrobial agents before they can reach their target.

There are several varieties of these efflux pumps but the one Professor Brown is targeting is specific to antiseptic disinfectant resistance, and is effective for more than 30 different compounds simultaneously.

“And not only that, it lives on a piece of DNA that can easily move between different bacteria and is usually carried with other antibiotic resistance mechanisms. So that one piece of DNA is spreading multiple resistance mechanisms. You can easily see how multidrug resistance comes about.”

Professor Brown’s work is truly a team effort – and an international one – with a group in Queensland computer modelling the protein to determine what will block it, a chemist in Perugia, Italy, making compounds to test, and another group over in Belgium studying the pump’s structure.

“So we're bringing it all together to come up with a holistic approach,” Professor Brown says. While results so far have been promising, Professor Brown holds no illusions that, even if she wins this battle, the war is ever going to be truly over.

“History shows that it's only ever been a few years after the introduction of something into the clinical space that the bacteria have become resistant to it. That’s why this multi-pronged approach is so important. All of the targets for antimicrobials are inside the cell, so if you’re trying to stop resistance we are going to have to hit not only pumps, but the mechanisms inside,” she says.

There is also a need to understand better how the bacteria work so we can develop new antimicrobial control agents.

“We have to come up with better public health measures to combat and reduce bacteria – handwashing is good and reduces that a lot, but we have to pay attention to how we wash and try to reduce overuse of antiseptics and disinfectants. “Good old soap and water’s just as good as anything, really.”