Could ‘probiotic’ plasmid drink combat antibiotic resistance?
The engineered strain, given in the form of a drink, contains engineered and patented DNA molecules - called plasmids – that could battle against antibiotic resistant bacteria.
Led by Professor Christopher Thomas from the University of Birmingham, the team is now seeking funding for a clinical trial for the drink – which they say has potential to work against many resistant bacteria commonly found in the human gut including E. coli, Salmonella and Klebsiella pneumoniae.
“Antibiotic resistance is one of the biggest medical challenges of our time,” said Thomas. “We need to be tackling this on a number of different fronts including by reducing our use of antibiotics and searching for new, more effective drugs.”
“Our approach, which tackles one of the causes of antimicrobial resistance at a genetic level, could be an important new weapon in this battle.”
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Plasmid are small circular DNA molecules that naturally exist in bacterial cells. They are distinct from chromosomal DNA and frequently carry genes that give resistance to antibiotics, which the bacteria are able to use.
Because plasmids replicate independently, they are able to spread between bacteria, carrying resistance genes with them.
By identifying and targeting plasmids responsible for antibiotic resistance, the team believe they have found a way to combat one of the greatest issues of our time.
“We were able to show that if you can stop the plasmid from replicating, then most of the bacteria lose the plasmid as the bacteria grow and divide. This means that infections that might otherwise be hard to control, even with the most powerful antibiotics available, are more likely to be treatable with standard antibiotics,” explained Thomas.
Thomas and his colleagues said the probiotic drink will contain bacteria in a similar way to normal probiotic drinks like Yakult. However, the bacteria in the drink will be carrying a newly engineered and patented type of plasmid – which the researchers call pCURE plasmids.
According to the Birmingham-based team, these work in two ways: they prevent the resistance plasmids from replicating and they also block a so-called ‘addiction system’ which the plasmids use to kill any bacteria that lose them.
This ‘addiction system’ works because plasmids responsible for resistance carry a stable toxin and an unstable antidote into the host cell. This means that if the plasmid is lost from the cell, the antidote breaks down but the harmful toxin remains to attack its host.
However, pCURE plasmids also carry the antidote, ensuring cells that lose the resistance plasmid survive and are able to thrive in the gut.
“We manipulated our pCURE plasmids to incorporate genes that block the replication of the resistance plasmid,” said Thomas. “We also target the plasmid’s addiction system by designing our pCURE plasmids to ensure the antidote is still available to the host.”
The study by Thomas and his team, published in PLOS One, shows that by doubling the number of copies of the pCURE plasmid in each bacterium, it became very effective at displacing different types of resistance plasmids and spread through laboratory cultures unaided, to clear out resistance.
By preventing the target plasmids from replicating, and displacing the resistance genes, the team effectively ‘re-sensitised’ them to antibiotics – something that Thomas and his team believe could be a promising solution to the growing battle against antibiotic bacteria.
Mouse data: A promising start
The team then collaborated with colleagues in the University of Sydney, Australia, to test the pCURE plasmids in mice.
Results showed that pCURE plasmids worked effectively, but that the mice needed to be ‘primed’ by giving the them an initial dose of antibiotic to reduce the number of competing bacteria.
“This is a promising start,” says Professor Thomas. “We aim to make modifications to further improve the efficacy of our pCURE plasmids before moving towards a first clinical trial.”
The next step is to see if the pCURE plasmids can replicate and spread fast enough in human volunteers to get rid of resistance plasmids.
Source: PLOS One
Published online, doi: 10.1371/journal.pone.0225202
“Potentiation of curing by a broad-host-range self-transmissible vector for displacing resistance plasmids to tackle AMR”
Authors: Alessandro Lazdins, et al