Solving the plasmid paradox: evolutionary advantages of multicopy plasmids

Today marks the end of 2016’s World Antibiotic Awareness Week, aimed to increase awareness of antibiotic resistance and to advocate for the prudent use of these drugs.

One of the key drivers of antibiotic resistance is how rapidly bacteria acquire DNA from the environment or from other bacteria. Resistance elements are often carried on mobile elements, DNA that can move around the genome or be transferred to other genomes. The almost universal rapid assimilation of DNA by bacteria leads to the acquisition of multiple antibiotic resistance genes in a variety of bacterial species. One such example of a DNA mobile element is the plasmid, small circular DNA that replicates independently of the chromosome and can be transferred from bacterium to bacterium during cell division, transformation, and conjugation.


The plasmid paradox

Though plasmids encoding antibiotic resistance elements benefit a bacterial population under selective pressure, it is unclear how plasmids persist in a population when not under selection. Replicating plasmids require energy and resources and burdens the cell with a fitness cost resulting in slower growth when compared to cells that do not carry plasmids. Moreover, some cells have even integrated genes from the plasmid in the chromosome allowing the bacterium to lose the plasmid. Thus, the long-term persistence of plasmids in bacteria remains perplexing.

Experimental evolution tracks bacterial adaptation to antibiotics

Millan and coworkers used experimental evolution to address this “plasmid paradox” by monitoring how Escherichia coli cells containing a multicopy plasmid behave when compared to cells that do not have the plasmid. The researchers inserted a multicopy plasmid encoding a beta-lactamase gene in one E. coli population and the same beta-lactamase gene into the chromosome of another E. coli population. Beta-lactamases break down beta-lactam antibiotics and makes the cell resistant to these drugs.

By comparing these two bacterial populations over time, they observed that the cells carrying the plasmid were able to grow at higher concentrations of antibiotic than the bacterial population encoding the beta-lactamase gene in the chromosome. This demonstrates an advantage of plasmid-encoded genes; genes expressed at higher levels can provide a greater fitness benefit to the cell under high selective pressure.

Many multicopy number plasmids are capable of being maintained at over 100 copies per cell. Due to the high number of the beta lactamase gene per cell, it can theoretically achieve several different mutations during replication than if there was just one copy in the chromosome. These gene variants are subsequently distributed into different cells during replication making some cells more resistant to antibiotics than before. After ~80 E. coli replication cycles, the researchers found that the high mutation rate of the beta-lactamase gene encoded on the plasmid allowed the bacterial population to become resistant to different beta-lactam antibiotics.

This work demonstrates the pivotal role plasmids play in bacterial evolution. Many antimicrobial resistance genes are carried on plasmids suggesting that understanding plasmid dynamics amongst bacteria in host or environmental reservoirs can lead to new treatment platforms for antibiotic resistant bacterial infections.

CC BY-NC-ND 4.0 Solving the plasmid paradox: evolutionary advantages of multicopy plasmids by Jennifer Tsang is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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