Regulatory fine-tuning of *mcr-1* increases bacterial fitness and stabilises antibiotic resistance in agricultural settings

Antibiotic resistance tends to carry fitness costs, making it difficult to understand how resistance can be maintained in the absence of continual antibiotic exposure. Here we investigate this problem in the context of mcr-1, a globally disseminated gene that confers resistance to colistin, an agricultural antibiotic that is used as a last resort for the treatment of multi-drug resistant infections. Here we show that regulatory evolution has fine-tuned the expression of mcr-1, allowing E. coli to reduce the fitness cost of mcr-1 while simultaneously increasing colistin resistance. Conjugative plasmids have transferred low-cost/high-resistance mcr-1 alleles across an incredible diversity of E. coli strains, further stabilising mcr-1 at the species level. Regulatory mutations were associated with increased mcr-1 stability in pig farms following a ban on the use of colistin as a growth promoter that decreased colistin consumption by 90%. Our study shows how regulatory evolution and plasmid transfer can combine to stabilise resistance and limit the impact of reducing antibiotic consumption.