Overuse of antimicrobials in livestock production can drive the evolution of bacteria more resistant to the first line of the human immune response, a new study says.
The results, published in the journal eLife, indicate that pigs and chickens could harbour large reservoirs of cross-resistant bacteria, capable of fuelling future epidemics.
Drug-resistant infections are one of the most serious threats to global health, with scientists saying there is an urgent need to develop new, effective antimicrobials.
One promising solution could be antimicrobial peptides (AMPs) - compounds naturally produced by most living organisms, including animals, and have important roles in innate immunity, our first line of defence against bacterial infections.
However, some AMPs are also used widely in livestock production, both to control infections and as growth promoters.
This has raised concerns that agricultural AMP use may generate cross-resistant bacteria that could then overcome the human innate immune response.
In this new study, led by the University of Oxford, researchers have demonstrated that evolution of such cross-resistant bacteria is not only possible, but also highly likely.
To test the idea, the researchers used colistin, an AMP produced by a bacterium (Bacillus polymyxa) that is chemically and functionally similar to AMPs produced in animals.
Colistin has become increasingly important as a ‘last-line of defence’ for treating infections caused by multidrug-resistant bacteria.
However, extensive use of colistin in livestock production since the 1980s has driven the spread of E.coli bacteria carrying mobile colistin resistance (MCR) genes.
In this study, E.coli carrying an MCR gene (MCR-1) were exposed to AMPs known to play important roles in innate immunity in chickens, pigs, and humans.
The bacteria were also tested for their susceptibility to human serum, which contains a complex cocktail of antimicrobial compounds, and for their ability to infect wax moth larvae (Galleria mellonella).
The study shows that anthropogenic use of antimicrobial peptides such as colistin can drive the accidental evolution of resistance to the innate immune system of humans and animals.
Scientists say this has major implications for the design and use of therapeutic antimicrobial peptides and suggests that resistant genes may be difficult to eradicate, even if antimicrobial peptide use in agriculture is withdrawn.
According to the researchers, cross-resistance to human AMPs is likely to be widespread, given that AMPs tend to have similar cellular targets and physico-chemical properties.
Pigs and chickens in agriculture are already known to act as important reservoirs of colistin-resistant E.coli.
Lead researcher Professor Craig MacLean said: "AMPs have been advocated as a promising alternative to antibiotics for treating bacterial infections.
"Using AMPs in this way will lead to the evolution of AMP resistance in pathogenic bacteria. Our results provide strong evidence that we will need to properly assess the impacts of resistance to new therapeutic AMPs on bacterial virulence before they are used to treat patients.
"If not, we will run the risk of accidentally arming pathogenic bacteria against our own immune system."
Cóilín Nunan, scientific adviser to the Alliance to Save Our Antibiotics, added that the study showed that colistin resistance was "probably even more dangerous than previously thought".
"It is astonishing that so many governments, like the UK’s, are refusing to ban colistin use in farming," he said.
"It is also remarkable that the British government is still opposed to banning preventative mass medication of intensively farmed animals with antibiotics, even though the EU banned such use over a year ago."
