Plasmid streamlining drives the extinction of antibiotic resistance plasmids under selection for horizontal transmission

Conjugative plasmids carrying antimicrobial resistance (AMR) genes are critical for the spread of AMR, due to their ability to transmit horizontally between bacterial hosts. We previously observed that during experimental evolution in the presence of abundant susceptible Escherichia coli hosts, the AMR plasmid R1 rapidly evolves variants with increased horizontal transmission due to mutations causing increased plasmid copy number. Yet AMR was progressively lost from the evolving populations. Here, we show that AMR loss was associated with evolution of streamlined plasmids in which the AMR region is spontaneously deleted, making plasmid carriage undetectable by plating on selective antibiotic-containing media. These plasmids transmit both vertically and horizontally more efficiently than the ancestral AMR plasmid, driving AMR extinction in bacterial populations and effectively acting as an intrinsic defence against AMR plasmids. A simple model of plasmid competition further shows that any horizontal or vertical transmission advantage conferred by plasmid streamlining would be enough to drive the displacement of competing AMR plasmids, with a given horizontal transmission advantage leading to faster replacement in conditions favoring horizontal transmission. Our results suggest that within-host plasmid evolution or engineered streamlined plasmids could be exploited to limit the spread of AMR in natural populations of bacteria.