Agricultural Antimicrobial Overuse Can Drive Evolution of Bacteria Resilient to Human Immune Primary Defenses

A new study led by the University of Oxford 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. The results, published today in the journal eLife, 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: ‘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.’

Dr Jessica Blair (University of Birmingham), Editor in Chief of NPJ Antimicrobials and Resistance (who was not involved in the study) said: ‘Antimicrobial peptides, including colistin, have been heralded as a potential part of the solution to the rise of multidrug-resistant infections. This study, however, suggests that resistance to these antimicrobials may have unintended consequences on the ability of pathogens to cause infection and survive within the host. This is particularly worrying because it suggests that E. coli carrying the MCR-1 gene may have a clear selective advantage even if the use of colistin is carefully controlled.’

Reference: Jangir PK, Ogunlana L, Szili P, et al. The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence. Cooper VS, Perry GH, Barbosa C, eds. eLife. 2023;12:e84395. doi:10.7554/eLife.84395

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