Pre-existing chromosomal polymorphisms in pathogenic E. coli potentiate the evolution of antibiotic resistance by MCR-1 plasmid acquisition

Bacterial pathogens show high levels of standing genetic diversity, but the influence of this diversity on the evolution of antibiotic resistance remains unclear. Here we address this problem in the context of colistin, a ‘last line of defense’ antibiotic. Using experimental evolution, we show that a plasmid carrying the MCR-1 colistin resistance gene dramatically increases the ability of E. coli populations to evolve high-level colistin resistance by acquiring mutations in lpxC, an essential chromosomal gene involved in lipopolysaccharide biosynthesis. Crucially, lpxC mutations increase colistin resistance in the presence of the MCR-1 gene, but decrease the resistance of wild-type cells, revealing positive sign epistasis for antibiotic resistance. Analysis of public genomic datasets shows that lpxC polymorphisms are common in pathogenic E. coli carrying MCR-1, highlighting the clinical relevance of this interaction. Importantly, lpxC diversity is high in pathogenic E. coli from regions with no history of MCR-1 acquisition, suggesting that pre-existing lpxC polymorphisms have potentiated the evolution of high-level colistin resistance by MCR-1 acquisition. More broadly, these findings highlight the importance of standing genetic variation and plasmid/chromosomal interactions in the evolutionary dynamics of antibiotic resistance.