Antimicrobial use in agriculture can breed bacteria resistant to first-line human defences
25 April 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).
- 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.’
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.’
Notes to editors:
For media enquiries and interview requests, contact: Professor Craig MacLean, email@example.com; 07703327882
The study ‘The evolution of colistin resistance 1 increases bacterial resistance to host antimicrobial peptides and virulence’ will be published in eLife on Tuesday 25 April at https://doi.org/10.7554/eLife.84395. This link will be active after the embargo lifts. To view a copy of the paper before this, contact Dr Caroline Wood: firstname.lastname@example.org
About the University of Oxford
Oxford University has been placed number 1 in the Times Higher Education World University Rankings for the seventh year running, and number 2 in the QS World Rankings 2022. At the heart of this success are the twin-pillars of our ground-breaking research and innovation and our distinctive educational offer.
Oxford is world-famous for research and teaching excellence and home to some of the most talented people from across the globe. Our work helps the lives of millions, solving real-world problems through a huge network of partnerships and collaborations. The breadth and interdisciplinary nature of our research alongside our personalised approach to teaching sparks imaginative and inventive insights and solutions.
Through its research commercialisation arm, Oxford University Innovation, Oxford is the highest university patent filer in the UK and is ranked first in the UK for university spinouts, having created more than 200 new companies since 1988. Over a third of these companies have been created in the past three years. The university is a catalyst for prosperity in Oxfordshire and the United Kingdom, contributing £15.7 billion to the UK economy in 2018/19, and supports more than 28,000 full time jobs.
The Department of Biology is a University of Oxford department within the Maths, Physical and Life Sciences Division. It utilises academic strength in a broad range of bioscience disciplines to tackle global challenges such as food security, biodiversity loss, climate change and global pandemics. It also helps to train and equip the biologists of the future through holistic undergraduate and graduate courses. For more information visit www.biology.ox.ac.uk