Bacteria can acquire and spread antibiotic resistance via small circular DNA molecules called plasmids. These self-replicating genetic units, which are not part of the bacterial genome, often carry antibiotic resistance genes that can be transferred between different bacteria. The EU-funded ‘Evolution of plasmid-mediated resistance in Pseudomonas aeruginosa’ (PLASREVO) project wanted to determine what drives the evolution and maintenance of plasmid-mediated antibiotic resistance. While antibiotic resistance-carrying plasmids benefit bacteria that are exposed to antibiotics, there is also a metabolic cost associated with being host to these genetic parasites. To understand why bacteria maintain plasmids even in the absence of antibiotic exposure, PLASREVO studied Pseudomonas aeruginosa, a bacterium that commonly causes infections in hospitals. Researchers used experimental and computational methods to show that interactions between multiple plasmids co-infecting the same bacterial cell aid the plasmids' survival. This suggests that plasmids co-evolve within environmental and clinical bacterial populations, helping to maintain each other's existence long after antibiotic use has been discontinued. While scientists used to think that plasmid survival depended on transmission between bacteria, recent work has shown that almost half of all plasmids are non-transmissible. Since these plasmids can be lost each time bacteria divide, PLASREVO experimentally evolved a highly unstable plasmid to show how it eventually stabilises within a population. Researchers found that bacterial populations rapidly overcame disadvantages to hosting plasmid parasites by incorporating compensatory mutations that allowed the bacterium to adapt to the plasmid. Antibiotic exposure further reinforced plasmid stability through positive natural selection, since antibiotic resistance genes provided a benefit to those bacteria carrying the plasmid. In a kind of feedback loop, benefits provided by the plasmid increased natural selection of bacteria containing compensatory mutations, and vice versa. This was because positive selection for the plasmid's antibiotic resistance gene increased the plasmid population size, while compensatory mutations in the bacterial genome increased plasmid stability. Understanding the evolutionary basis for maintenance of plasmid-mediated antibiotic resistance in bacterial populations will help to develop new strategies to combat this serious health threat.
Antibiotic resistance, plasmids, bacteria, Pseudomonas aeruginosa, compensatory mutations