Pre-existing polymorphisms in pathogenic E. coli potentiate the evolution of antibiotic resistance

Many bacterial pathogens show high levels of genetic diversity, but the influence of this standing genetic variation on the evolution of antibiotic resistance remains unclear. Here we use a combination of experimental evolution and population genomic analysis to test for potentiator genes that accelerate the evolution of resistance to colistin, a last line of defence antibiotic. Using experimental evolution, we show that the presence of the MCR-1 colistin resistance gene dramatically increases the ability of E. coli populations to evolve high-level colistin resistance via the acquisition of mutations in lpxC, an essential gene involved in lipopolysaccharide biosynthesis. lpxC mutations decrease resistance to colistin in a wild-type background, but increase resistance in the presence of MCR-1, demonstrating positive sign epistasis for colistin resistance. Analysis of genomic datasets shows that lpxC polymorphisms are common in pathogenic E. coli carrying MCR-1, suggesting that this interaction is leads to high-level colistin resistance in pathogenic E. coli. Crucially, lpxC polymorphisms are abundant in pathogenic E. coli from regions with no history of MCR-1 carriage, suggesting that pre-existing lpxC polymorphisms potentiated the evolution of high-level colistin resistance in pathogenic E. coli. More broadly, these findings highlight the importance of standing genetic variation in the evolutionary dynamics of antibiotic resistance.