Chance favors the prepared genomes: horizontal transfer shapes the emergence of antibiotic resistance mutations in core genes

Bacterial lineages vary in the frequency with which they acquire novel traits, like antibiotic resistance or virulence. While previous studies have highlighted the impact of the genetic background on the successful acquisition of novel traits through horizontal gene transfer, the impact of the latter on the subsequent evolution of bacterial genomes by point mutations remains poorly understood. Here, we studied the evolution of resistance to quinolones in thousands of Escherichia coli genomes. Resistance-conferring point mutations in the core genes are frequent and accumulate very quickly. We searched for gene gains and losses significantly associated with the subsequent acquisition of these resistance mutations. This revealed 60 groups of genes in genetic linkage whose gain or loss induced a change in the probability of subsequently becoming resistant to quinolones by point mutations in gyrA and parC . Although some of these chronologies may reflect epidemiological trends, most of these groups encoded functions that were previously associated with antibiotic resistance, tolerance, or persistence, often specifically under quinolone treatment. A lot of the largest groups were found in prophages or plasmids, and they usually increased the likelihood of subsequent resistance mutations. Conversely groups of lost genes were typically small and chromosomal. Quinolone resistance was among the first resistances acquired in the extant lineages of E. coli and its acquisition was associated with an increased likelihood of acquiring other types of resistances, including to aminoglycosides and beta-lactams. Our findings suggest that gene flow shapes the subsequent fixation rate of adaptive mutations in core genes. Given the substantial gene flow within bacterial genomes, interactions between horizontal transfer and point mutations in core genes may be key to the success of adaptation processes. ### Competing Interest Statement The authors have declared no competing interest.