Bacterial strain structure shapes the trajectory of antibiotic resistance genes from plasmid to chromosome

The evolutionary dynamics determining whether an antimicrobial resistance (AMR) gene resides on a plasmid or a chromosome are critical to understanding the spread of resistance. While theoretical models often predict that beneficial traits should ultimately integrate into the more stable chromosome, contemporary genomic data frequently shows a strong enrichment of resistance genes on mobile, yet costly and less stable plasmids. Here, we propose that the widespread plasmid-mediated resistance observed today may not represent a stable evolutionary equilibrium, but rather a snapshot of an ongoing process. Using a stochastic multi-strain model, we explore the role of strain diversity as a determinant of the timescale of this process. We suggest that the population structure of the bacterial host species, maintained by balancing selection, acts as a substantial barrier to the selective sweep of vertically transmitted chromosomal genes. Because horizontal transmission allows conjugative plasmids to readily cross these strain boundaries, our model indicates that plasmid-borne resistance can transiently dominate the population before chromosomal integration takes over, and that this transient dominance can last for decades. We illustrate these predictions by analysing antimicrobial resistance gene location in three common opportunistic gut pathogens. Furthermore, we show how extending the model to include co-selection between resistance genes on multi-drug resistance plasmids can lead to more complex dynamics that transiently reverse this plasmid-to-chromosome trajectory. Overall, our findings highlight how bacterial population structure can dictate the evolutionary trajectory of beneficial genes, suggesting that the current distribution of AMR genes between chromosome and plasmids is a prolonged transient state rather than a static endpoint.