Antimicrobial Use In Agriculture Can Breed Bacteria Resistant To First-Line Human Defences

Apr 26, 2023

A new study has shown that overuse of antimicrobials in livestock production can drive the evolution of bacteria more resistant to the first line of the human immune response.
Bacteria that had evolved resistance to colistin, an antimicrobial widely used in farming, also showed resistance to compounds that are key components of human and animal immune systems.
The results indicate that farmed 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, and there is an urgent need to develop new, effective antimicrobials. One promising solution could be antimicrobial peptides (AMPs). These are 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).

Key findings:

On average, the MCR-1 gene increased resistance to host AMPs by 62%, compared with bacteria lacking the gene. This increased resistance provided a strong selective advantage to the MCR-1 gene in the presence of AMPs.
Similarly, E. coli carrying MCR-1 were at least twice as resistant to being killed by human serum.
E. coli carrying MCR-1 had increased virulence on wax moth larvae, compared with control strains lacking the gene. Larvae injected with MCR-1 E. coli showed an approximately 50% reduced survival, compared with larvae injected with control E. coli.

The results demonstrate that use of bacterial AMPs in agriculture can generate broad cross-resistance to the human innate immune response.

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 (Department of Biology, University of Oxford) said: ‘Our study clearly shows that anthropogenic use of AMPs such as colistin can drive the accidental evolution of resistance to the innate immune system of humans and animals. This has major implications for the design and use of therapeutic AMPs and suggests that resistant genes may be difficult to eradicate, even if AMP use in agriculture is withdrawn.’

He added: ‘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 (who were not involved in the study) said: ‘This new study shows that colistin resistance is 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. 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.’

Click here to see more...

Video: The 15-Year Bet Behind Every New Variety!

Canada is trying to decide how much agricultural research capacity it can afford to lose. Brian Rossnagel believes the better question is whether the country can afford to rebuild it.

The longtime barley and oat breeder makes the case with a simple fact about his profession: the consequences of today’s decisions may not become visible for 10 or 15 years.

“Pick the right parents. That’s the biggest thing,” Rossnagel says. “If you pick the wrong parents, you’re not going to get anywhere—and you don’t know that until 10 years, 15 years later.”

That warning carries particular weight as Agriculture and Agri-Food Canada moves to reduce spending and streamline parts of its science operations. The department’s 2026–27 plan anticipates the loss of approximately 665 positions by 2028–29 and says some research will be reduced where capacity exists in academia or industry. AAFC says the changes will make its science operations more cost-effective over the long term.

For Canada’s seed industry, Rossnagel’s career illustrates what is at stake.

This fall, the retired University of Saskatchewan breeder will be inducted into the Canadian Agricultural Hall of Fame. During his 35-year career at the Crop Development Centre, he helped develop more than 100 barley and oat varieties, including CDC Austenson—one of Western Canada’s most widely grown feed barleys. His induction recognizes not only those varieties, but the collaboration and research system that made them possible.

Rossnagel is quick to emphasize that none of it was the work of one person.

“The first thing I thought about was all the other people who contributed to whatever success I and my program had over the years,” he says. “We know that it’s not an individual who does this. It’s a group—a team.”

That team extends well beyond the breeder whose name appears beside a variety. It includes technicians, pathologists, quality specialists, statisticians, regional testing sites, seed growers and industry partners. It also includes the breeders who came before and those who will carry the germplasm forward.

CDC Fraser barley, for example, moved through three breeding careers. Its parents came from Brian Harvey’s program. Rossnagel advanced the material after Harvey retired, and Aaron Beattie later guided it through registration and release.

That kind of handoff is normal in plant breeding. The person who makes the original cross may never see the resulting variety reach farmers.

It also explains why lost research capacity cannot simply be switched back on when budgets improve.

“If you shut it off, it’s very, very difficult—and particularly costly—to start it up again,” Rossnagel says. “If you have to start from scratch, it’s going to be at least 10 years before anybody notices whether you’re getting anything done or not.”

The concern is not simply how many experimental lines Canada can process. Modern equipment, statistical tools and genetic technologies allow today’s breeding programs to evaluate tens of thousands of lines—far more than Rossnagel could handle when he entered the field in the early 1970s.

But efficiency and automation do not generate every idea.

“If you pare back down, and instead of having six or seven individual scientists concentrating on wheat breeding, you go down and say three people could handle all this, well, that’s half the ideas gone,” he says. “Particularly if you happen to lose the three people who had the really neat and innovative ideas, boy, that’s a problem.”

It is a timely distinction for Canadian agriculture. Consolidating programs may preserve the volume of material moving through a system, at least initially. It may not preserve the diversity of thinking, regional knowledge or willingness to pursue unconventional crosses.

That regional knowledge matters because Canadian agriculture is not one uniform production environment. A variety suited to southern Alberta may face different disease, moisture and maturity pressures than one grown in Manitoba, Ontario or Atlantic Canada.

“Agriculture is applied biology,” Rossnagel says. “Biology, all around the Earth, moves from the poles to the equator. It does not move from Newfoundland to B.C. like politics do.”