Good bugs to battle C difficile and MRSA

A UCC researcher is involved in a new kind of germ warfare, developing genetically engineered probiotics for use against hospital superbugs

A RESEARCH group in Cork has enlisted a new ally in the fight against hospital superbugs – designer bacteria. They are building tougher bacteria as a way to tackle the dangerous Clostridium difficile.

It is germ warfare out there as researchers do battle against the new emerging superbugs, says University College Cork's Dr Roy Sleator. Many have developed resistance to our best antibiotics leaving doctors without weapons that can stop C difficileand the infamous MRSA.

He and colleagues at UCC's Alimentary Pharmabiotic Centre (APC) are taking an alternative approach, adding extra genes that will give their designer bacteria the edge over C difficile.

“The story begins 10 years ago when we looked at pathogens like listeria and how they survive in a harsh environment like the gut,” explains Sleator, a Health Research Board and APC principal investigator who collaborates with APC’s Prof Colin Hill.

Listeria can survive the acid and bile encountered in the gut, but beneficial probiotics, bacteria that deliver a health benefit, were immediately killed off. “Our thinking was if we could apply what the pathogen has evolved, we could breed a new kind of probiotic,” he says.

They started experimenting with Lactobacillus salivarus, a bacterium selected from a collection of organisms held at UCC and known to have beneficial probiotic effects.

The APC looks for “good bugs” in the most unexpected of places. Gut tissue samples recovered from consenting patients offer a ready supply, but so too does the contents of an infant’s nappy. “They are quite good sources for probiotics,” says Sleator.

L salivarusis particularly useful for their purposes, he states. "One of the major reasons for choosing it is it is genetically amenable to expressing genes from other sources. We can pretty much make it do anything we want."

Teaching it to survive in the gut is an example. “All of this is possible by adding just one or two genes. The amount of genetic engineering is really quite simple, it is just having the right genes to put in.”

One of the genes they want to build in is particularly valuable, producing a bacteria killing substance or bacteriocin that specifically attacks C difficile.

The researchers are also trying to deceive the superbug by having the engineered probiotic act as a decoy, making the C difficileconnect to the decoys rather than infecting healthy tissues, Sleator explains.

C difficilecolonises a host by attaching itself to cells and infecting them, releasing a powerful toxin that kills the host cell.

"We aim to engineer the [probiotic] strain to express decoy receptors on the surface and fool the C difficileinto attaching to it instead of the host cell. It is also binding the toxin," Sleator says.

The probiotic in effect will “mop up” the infection and prevent the toxin from damaging host cells.

Using a probiotic in this way confers other advantages, he says. The powerful antibiotics needed to control superbugs also tend to wipe out the “good bacteria” normally found in the gut.

C difficileis generally a poor competitor against other bacterial strains, but if the field is left clear through antibiotic use, it spreads readily, just like a garden weed will move into space cleared of competing plants.

The probiotics do not cause a clear-out of good bacteria however, making it tougher for the C difficileto take hold and do its damage.

APC researchers are also looking at the use of probiotics as an innovative new way to deliver vaccines. It would allow a person to swallow the vaccine rather than face an injection, making vaccinations simpler, safer and certainly less painful.

Sleator's team of eight includes PhD and Masters students and also a post doctoral researcher. He has been selected to serve as editor in chief of the journal, Bioengineered Bugs, published by Landes Biosciences in Texas. His first issue will be out in January 2010.