Drug-resistant infections are one of the most serious threats to global health, and there is an urgent need to develop new and 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 defense against bacterial infections.
However, some AMPs are also widely used in livestock production, both for infection control and growth promotion. This has raised concerns that the agricultural use of AMP could 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 shown that the evolution of such cross-resistant bacteria is not only possible, but highly probable.
To test the idea, the researchers used colistin, an AMP produced by bacteria (polymyxa bacillus) that is chemically and functionally similar to AMPs produced in animals. Colistin has become increasingly important as a “last line of defense” for the treatment of infections caused by multi-resistant bacteria. However, the extensive use of colistin in livestock production since the 1980s has fueled the spread of E.coli bacteria carrying mobile colistin resistance (MCR) genes.
In this studio, E.coli carrier of an MCR gene (MCR-1) were exposed to AMP which is known to play an important role in innate immunity in chickens, pigs and humans. The susceptibility of the bacteria to human serum, which contains a complex cocktail of antimicrobial compounds, and their ability to infect wax moth larvae (melonella gallery).
Key results:
- On average, the MCR-1 The gene increased the host’s AMP resistance by 62%, compared to bacteria lacking the gene. This increased resistance provided a strong selective advantage to MCR-1 gene in the presence of AMP.
- Similarly, E.coli that carries MCR-1 they were at least twice as resistant to being killed by human serum.
- E.coli that carries MCR-1 it had increased virulence in wax moth larvae, compared to control strains lacking the gene. larvae injected with MCR-1 E.coli showed reduced survival of approximately 50%, compared to control-injected larvae E.coli.
The results demonstrate that the use of bacterial AMP in agriculture can generate extensive cross-resistance to the human innate immune response.
According to the researchers, cross-resistance to human AMPs is likely widespread, since AMPs tend to have similar cellular targets and physicochemical properties. Pigs and chickens in agriculture are already known to act as important reservoirs for colistin-resistant bacteria. E.coli.
Lead investigator Professor Craig MacLean (Oxford University Department of Biology) said: “Our study clearly shows that anthropogenic use of AMP such as colistin may drive the accidental evolution of resistance to the innate immune system of humans and animals”. This has important implications for the design and use of therapeutic MPAs and suggests that resistance genes may be difficult to eradicate, even if MPA use in agriculture is withdrawn.’
He added: ‘MPAs have been championed as a promising alternative to antibiotics for treating bacterial infections. The use of AMP in this manner 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 weaponizing pathogenic bacteria against our own immune system.”
Cóilín Nunan, Scientific Advisor at the Alliance to Save Our Antibiotics (who was not involved in the study) said: ‘This new study shows that colistin resistance is probably even more dangerous than previously thought. It is surprising that so many governments, such as the UK, refuse to ban the use of colistin in agriculture. It is also notable that the British government is still opposed to banning preventive mass medication with antibiotics in intensively farmed animals, despite the fact that 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 increased of multidrugs”. -resistant infections. However, this study suggests that resistance to these antimicrobials may have unintended consequences on the ability of pathogens to cause infections 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 colistin use is carefully controlled.’
—————————————————-
Source link