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

Abstract

AbstractAntibiotic 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 ofmcr-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 ofmcr-1, allowingE. colito reduce the cost ofmcr-1while simultaneously increasing colistin resistance. Conjugative plasmids have transferred low cost/high resistancemcr-1alleles across an incredible diversity ofE. colistrains, further stabilizingmcr-1at the species level. Crucially, regulatory mutations were associated with increasedmcr-1stability 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.