Antimicrobial overuse in agriculture can drive the evolution of bacteria more resistant to the first line of human defences, warned scientists.
Antimicrobial resistance "threatens" the very core of modern medicine and the sustainability of an effective, global public health response to the enduring threat from infectious diseases, the World Health Organisation (WHO) alerted, and warned that "few replacement products are in the pipeline".
Professor Dame Sally Davies, UK special envoy on antimicrobial resistance, had also warned when she was England's Chief Medical Officer, that antimicrobial resistance (AMR) was "one of the main threats to the country, alongside terrorism and pandemic".
The authors of a new study, published in eLife, echoed these fears and said that and there is an urgent need to develop new, effective antimicrobials to treat drug-resistant infections.
In July last year, the Department of Health and Social Care (DHSC) announced an additional £4.5 million investment by the UK to help tackle the drug-resistant infection pandemic, taking the UK's total investment to support the Global Antibiotic Research and Development Partnership (GARDP) to nearly £19 million.
"One promising solution could be antimicrobial peptides (AMPs)," proposed the authors.
Game Keeper to Poacher
AMPs 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", they explained. They are potent antimicrobials with desirable pharmacodynamic properties, and a low rate of resistance evolution, highlighted the authors.
Dr Jessica Blair, University of Birmingham and editor-in-chief of NPJ Antimicrobials and Resistance, who was not involved in the study, commented that antimicrobial peptides, including colistin, had been heralded as a potential part of the solution to the rise of multidrug-resistant infections.
However, some AMPs are also used widely in livestock production, both to control infections and as growth promoters. This, the authors explained, had raised concerns that agricultural AMP use may trigger a collateral effect of generating cross-resistant bacteria that could then overcome the human innate immune response.
For the study, researchers, led by the University of Oxford, set out to test this hypothesis. The researchers measured the resistance of MCR-E coli to a panel of AMPs and, given the importance of agricultural animals as reservoirs of MCR, they tested AMPs involved in the innate immunity of chickens, pigs, and humans.
They used the AMP colistin produced by Bacillus polymyxa, which they said was 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," they pointed out. However, extensive use of it in livestock production had driven the spread of E coli bacteria carrying MCR genes.
Accidental Evolution of Resistance
Bacteria that had evolved resistance to colistin also showed resistance to compounds that are key components of human and animal immune systems, said the researchers.
They identified that on average, the MCR-1 gene increased resistance to host AMPs by 62%, compared with bacteria lacking the gene. Similarly, E coli carrying MCR-1 were at least twice as resistant to being killed by human serum.
The results demonstrated that use of bacterial AMPs in agriculture "can generate broad cross-resistance to the human innate immune response", they said, and that farmed pigs and chickens could harbour large reservoirs of cross-resistant bacteria, capable of fuelling future epidemics, they warned.
Professor Craig MacLean, department of biology, University of Oxford, and lead researcher, 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."
According to the researchers, cross-resistance to human AMPs is likely to be widespread, given that AMPs tend to have similar cellular targets and physicochemical properties.
"The evolution of such cross-resistant bacteria is not only possible, but also highly likely," the researchers presaged.
Professor MacLean emphasised that this had major implications for the design and use of therapeutic AMPs. He worried that resistant genes may be difficult to eradicate, even if AMP use in agriculture is withdrawn.
Cóilín Nunan, scientific adviser to the Alliance to Save Our Antibiotics, which was not involved in the study, said: "This new study shows that colistin resistance is probably even more dangerous than previously thought.
"AMPs have been advocated as a promising alternative to antibiotics for treating bacterial infections," reiterated Professor MacLean. However, he cautioned that using AMPs in this way "will lead to the evolution of AMP resistance in pathogenic bacteria".
Dr Blair stressed 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."
Professor MacLean indicated the need properly to assess the impacts of resistance to new therapeutic AMPs on bacterial virulence before they were used to treat patients. "If not, we will run the risk of accidentally arming pathogenic bacteria against our own immune system," he forewarned.
Funding for the study was provided by the Wellcome Trust, Medical Research Council, National Natural Science Foundation of China, European Research Council and Hungarian Academy of Sciences Momentum 'Célzott Lendület' Programme, National Research, Development, and Innovation Office 'Élvonal' Programme, National Laboratories Program, and National Research, and the Development and Innovation Office, Hungary. No conflicts of interests declared.