Regulatory fine-tuning and horizontal gene transfer stabilize mobile colistin resistance

Abstract

Antibiotic resistance tends to carry fitness costs, making it difficult to understand how resistance can be stably maintained in pathogen populations over the long-term. Here, we investigate this problem in the context of mcr-1, a fitness-costly gene that confers resistance to the last-resort antibiotic, colistin. Here we show that regulatory evolution has fine-tuned the expression of mcr-1, allowing E. coli to reduce the 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 stabilizing mcr-1 at the species level. Crucially, 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 the rapid evolution and horizontal transmission of resistance genes can combine to stabilize resistance and reduce the efficiency of interventions aimed at reducing AMR by limiting antibiotic consumption.