Not enough to reduce antibiotic use in animal feed to combat resistance

The study, led by the University of Oxford, underlines the importance of understanding the regulatory evolution of resistance genes to strategically combat antimicrobial resistance (AMR).

Protect ‘last-line’ antibiotics

The issue is a particularly serious one with AMR a growing threat to global health, with at least 1.2m people dying each year due to drug-resistant infections. The overuse and misuse of antibiotics is a major driver of AMR and there is an urgent need to protect the efficacy of “last-line” antibiotics to treat multidrug resistant infections.

The Chinese government banned the use of the antibiotic of last resort colistin as a growth promoter in animal feed in 2017 in response to the rapid spread of antibiotic resistant bacteria – Escherichia coli (E. coli) carrying mobile colistin resistance (MCR) genes. Bacteria carrying MCR genes are resistant to treatment with colistin and cause hard to treat drug-resistant infections in humans and animals.

While the ban led to a 90% reduction in colistin consumption, large scale surveillance studies across China have found that the decline in the mcr-1 gene was slower than anticipated.

Our results provide strong evidence that the evolution of the mcr-1 gene has helped to stabilise colistin resistance in agricultural settings, even though colistin use in agriculture had declined by 90%.

Research into why decline slower than expected

This led researchers from Oxford University’s Department of Biology to explore this discrepancy by focusing on the regulatory region of DNA that controls the expression of the mcr-1 gene. They found that this region shows high levels of variation, and that certain variants were able to offset the fitness costs of the mcr-1 gene. By fine-tuning mcr-1 expression to a lower level, these variants enabled the bacteria to achieve high growth ates while simultaneously increasing colistin resistance.

They then analysed DNA sequence data from E.coli carrying mcr-1 from before and after the colistin ban. This revealed that the regulatory mutations that increased fitness in the lab had remained stable in E.coli populations from farms, and had hardly declined in response to the ban.

Lead researcher Professor Craig Maclean, Professor of Evolution and Microbiology at the University of Oxford, said: “Our results provide strong evidence that the evolution of the mcr-1 gene has helped to stabilise colistin resistance in agricultural settings, even though colistin use in agriculture had declined by 90%. This finding is of major importance for all future interventions targeting the reduction of antibiotic usage, demonstrating the need to consider the evolution and transmission of genes to introduce viable strategies to reduce resistance.”

Professor Tim Walsh, Director of Biology at the Ineos Oxford Institute and co-author on the paper, added: “Colistin resistance across many strains of E.coli and in diverse environments from pig farms to hospital wards should act as our warning of the dangers of antibiotic overuse and misuse.

“It is not enough to reduce antibiotic consumption to effectively combat antibiotic resistance. We need urgent and innovative approaches to combat antibiotic resistance, and new strategies to protect our last-resort antibiotics for when we need them most.”

The study, “Regulatory fine-tuning of mcr-1 increases bacterial fitness and stabilises antibiotic resistance in agricultural settings,” has been published in the Journal of the International Society for Microbial Ecology (ISME).