Switching on to 'superbugs'

IT’S ONE of the most famous stories of serendipitous discovery in science: in 1928 Alexander Fleming left some bacterial cultures on the lab bench when he went on holiday, an oversight that led to the development of penicillin when he returned home and made his observations of the contaminated plates.

In the decades since, antibiotics have saved countless lives and have been cited as one of the main reasons for increased life expectancy in some parts of the world.

But even while receiving the Nobel nod from Stockholm in 1945, Fleming struck a note of caution. During his speech accepting the prize he said: “The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.”

He was making an important point. Today we share the world with several strains of disease-causing bacteria that have developed resistance to antibiotics, including MRSA, strains of E.coli and Pseudomonas aeruginosa. We often refer to these as superbugs, though not everyone is fond of the term.

“It suggests that there’s something extraordinary about a bug that has antibiotic resistance,” says Martin Cormican, professor of bacteriology at NUI Galway School of Medicine. “But what’s extraordinary is the extent to which bacteria will adapt to anything you throw at them. If you pour water into a cup the water isn’t clever because it took the shape of the cup. Likewise, the nature of bacteria is to adapt quickly, and because we have shaped the cup in a way that makes antibiotic resistance advantageous, the bacteria have taken that shape.”

According to Prof Cormican,bacteria can adapt because they proliferate so quickly, some species generating new cells every 20 minutes, and also because tiny errors can crop up between mother cells and daughter cells.

“Every time a single E.coli cell copies itself and makes two, there is an error rate. Any daughter cell has probably 400 or 500 tiny differences from the mother cell it came from,” he says. “And because they multiply every 20 minutes that is one way to have change happening all the time.”

Another route for bacteria to acquire the genetic tools to resist antibiotics is through “horizontal” gene transfer, he adds. This process involves chunks of genetic material shuffling between cells.

“It’s like cutting and pasting in a word processor,” he says. “They can cut and copy a set of genes in one organism and paste it into another.”

Understanding how our bodies respond to problematic bacteria is one way of figuring out how to handle them. Dr Christine Loscher, a senior lecturer in immunology at Dublin City University (DCU), has been working out how the bacterium Clostridium difficile ( C difficile) interacts with our immune system. A hardy bug that can be a problem in healthcare settings, C difficileis a slightly different type of "superbug": it may live harmlessly in the gut, but if it flourishes there, perhaps after a person has been on antibiotics, its toxins can cause severe symptoms in some patients.

“One of the ways to understand an infection is to figure out how it is recognised by your immune system, what it switches on in your immune system in order for your immune system to be able to clear it,” says Loscher.

She and colleagues at DCU and Trinity College Dublin recently discovered that particular surface-layer proteins on C difficileappear to trip a switch in our immune systems called Toll-like receptor 4 (TLR4). The group's research, funded by Science Foundation Ireland, looked at how proteins from C difficileinteract with immune cells in the lab and at how models that lacked components of an immune response reacted to the bug. Overall, TLR4 was pinpointed as an on signal for responding to and fighting the bacterium.

"We showed that it was the recognition system for C difficile, and where you had a model where you didn't have it present to recognise the bug, you got a really severe infection," says Loscher of the research results, published recently in the journal PLoS Pathogens.

The team is now extending the work to look at patient samples. Its findings could inform new ways to identify at-risk patients, or even point to new therapies.

“You want to develop a way of figuring out whether patients are susceptible to infection by looking at the components of their recognition system,” says Loscher. “And also to see whether you can design a therapy switch on the right immune response to clear an infection.”

Meanwhile, researchers in Cork have identified an agent that can kill C difficile. They found it by screening 30,000 strains of bacteria cultured from the gut. This search led them to the strain Bacillus thuringiensis, which produces an antimicrobial agent, according to Mary Rea, a microbiologist and research officer at Teagasc Food Research Centre, Moorepark.

"We have been able to purify this [agent] in the laboratory and have shown that its spectrum of inhibition is narrow in that is it only kills C difficileand closely related organisms," she says. "That is what we were looking for, as we wanted something that specifically targeted C difficileand would not have an effect on the wider flora of the gut."

The researchers then put the agent, called Thuricin CD, to the test in a lab model of the distal colon, which is the site of C difficileinfection. This test found that Thuricin CD compared well with commonly used antibiotic treatments against the bacterium. It appears also that Thuricin CD isn't as hard on other bugs that patients might want to keep.

"We have shown that Thuricin CD does not kill lactobacillusand bifidobacteriawhich are normally considered beneficial to gut health," says Rea.

Details of the research, which involved scientists from the SFI-funded Alimentary Pharmabiotic Centre and the University of Alberta, were published last year in the journal Proceedings of the National Academy of Sciences. Thuricin CD has been licensed to the company Alimentary Health Ltd, according to Rea, and work is continuing to develop a delivery system for the antimicrobial.

Triple whammy: how plasma technology could wipe out bugs

ZAPPING BUGS with plasma – it sounds like the stuff of movies, but a new research project is putting the idea to the test, in the hope that it could help clean up hospitals.

Decontamination is critical for preventing hospital-acquired infections, but current methods aren’t always optimal, according to the Dublin City University (DCU) lecturer Stephen Daniels, who is also executive director of the National Centre for Plasma Science and Technology. “They rely on high temperatures or potentially toxic chemicals, or some components of the hospital environment are not readily amenable to regular and effective decontamination.”

The new research project, a collaboration between DCU and Prof Hilary Humphreys at the Royal College of Surgeons, is looking to kill hospital reservoirs of bugs, such as MRSA (pictured) and Clostridium difficile, with gaseous plasma.

“Plasma technology is a wide-spectrum killer,” says Daniels, describing an approach that is thought to kill bugs by hitting them with a triple whammy. Ultraviolet radiation, something that can be lethal to microbes, is produced by the technology. Chunks then get knocked out of the microbes because the new system produces highly reactive chemicals. And, finally, bugs get bombarded by highly energetic particles given off by the plasma. Few can survive the onslaught.

The three-year project, funded by Science Foundation Ireland and the Health Research Board, will develop the plasma technology in the lab and will later trial it in hospitals. One result may be a hand-held decontamination device, according to Daniels.