Probiotics fighting antibiotic resistance: Researchers engineer strains to tackle resistant bacteria

16 Jan 2020 --- The next decade could see the commercialization of a new probiotic drink with a specifically engineered genetic element to help fight antibiotic-resistant bacteria. By targeting small DNA molecules called plasmids, a team of scientists at the University of Birmingham, UK, has managed to displace the resistance genes available to the bacteria, effectively “re-sensitizing” them to antibiotics. The researchers have patented the key genetic element and are now seeking funding for a clinical trial for the drink, which has the potential to work against resistant bacteria, such as E. coli, Salmonella and Klebsiella pneumoniae.

“We certainly plan to commercialize if we are able to carry out human clinical trials and if these are sufficiently encouraging. The first stage would be to test for plasmid spread in healthy human volunteers. However, for this, we believe we need more effective ways of ‘self-destructing’ the plasmid in the human volunteer at the end of the trial. I can see clinical trials lasting three to five years, and then there being potentially five more years to commercial availability,” Christopher Thomas, Professor of Molecular Genetics at the University of Birmingham and lead researcher of the project, tells NutritionInsight.

Plasmids within bacterial cells often carry genes that give resistance to antibiotics, which the bacteria are able to use. Normally, the plasmids replicate independently, spreading between bacteria and carrying resistance genes with them. However, the researchers prevented the target plasmids from replicated, allowing for the displacement of the available resistance genes. These new plasmids have been dubbed pCURE plasmids, with the process being published in PLOS One. 

In addition to stopping the resistance plasmids from replicating, the pCURE plasmids also block a so-called “addiction system,” which the plasmids use to kill any bacteria that lose them. In this system, the resistance plasmid carries a stable toxin and an unstable antidote into the host cell. If the plasmid is lost from the cell, the antidote breaks down, leaving the harmful toxin to attack its host. pCURE plasmids also carry the antidote, ensuring that cells that lose the resistance plasmid survive and proliferate in the gut. 

During the research process, it was also found that doubling the number of copies of the pCURE plasmid in each bacterium made displacing different types of resistance plasmids very effective. The pCURE plasmids could then also spread through laboratory cultures unaided, to clear out resistance. This process has been tested in mice, where it was found that the plasmids need to be “primed” by giving the mice an initial dose of the antibiotic to reduce the number of competing bacteria.

The product would likely be similar to Mutaflor, which is available as a suspension or in capsules.Challenges around genetic manipulation
So far, the team has delivered the pCURE plasmid from a probiotic E. coli strain that is commercially available under the trade name “Mutaflor.” This can be taken as a suspension or in the form of capsules. “We anticipate that our drink would, therefore, be very similar to Mutaflor. The key difference would be that the pCURE plasmid would then spread into the gut bacteria and displace the resistance plasmids that we want to get rid of,” says Thomas.  

However, he continues that the team anticipates facing challenges around the fact that the new element is the result of genetic manipulation. This means that there are questions around the potential risks of this technology versus the benefits to healthcare by making it easier to treat infections.

Nonetheless, he notes that the health industry is facing a crisis as the number of untreatable infections increases due to antibiotic resistance, although this problem is being addressed on many fronts. “Displacing genetic elements carrying resistance genes is just one of the novel approaches being considered. We think it would be most effective as a preventative measure with individuals who are at increased risk of infection and have been identified as carrying resistant bacteria already. At this stage, we do not see it as a way of treating infections that are already a problem,” explains Thomas. 

Up until this point, the team has only focused on this single application. However, there is potential for delivering other beneficial properties to gut bacteria. However, this will depend on perfecting a system that ensures the efficient spread of pCURE throughout the gut bacteria. 

Probiotics have been an area of great interest recently. Last month, researchers found that dead Lactobacillus paracasei (D3-5) reduces age-related leaky gut in older mice as effectively as the live strain. The team has highlighted the human potential for the postbiotic strain as a supplement or as a functional food and beverage ingredient, with commercialization expected in mid-2020. 

However, probiotics and prebiotics may impact the microbiome of male infants differently to female infants, according to another study last December. Scientists found that piglets produced very different levels of immune cells, antibodies and other immune-associated molecules depending on their sex. 

By Katherine Durrell