For bacteria, addiction to DNA can be a life or death situation. Lose that DNA and the bacterium suffers an unfortunate toxic death.
Many bacteria easily transfer DNA amongst themselves in the forms of plasmid DNA. Plasmids are mobile genetic elements that replicate independently of the chromosome. These small circular pieces of DNA often contain genes that provide its carrier a survival advantage under specific environmental conditions. For example, if a bacterium contains a plasmid with an antibiotic resistance gene, it can survive antibiotic treatment. But, the plasmid is not beneficial to its host cell in all situations and poses a metabolic burden for the host. So why do these plasmids exist and remain in bacteria?
Plasmids have evolved many mechanisms to ensure their survival. One such mechanism is through plasmid addiction systems. Plasmid addiction systems make sure that dividing cells only survive if they obtain a plasmid. If they don’t, they die.
What is a Plasmid Addiction System?
Many plasmid addiction systems consist of a paired toxin and anti-toxin. The toxin is stable while the anti-toxin is unstable and is degraded and destroyed by enzymes in the cell. If a replicating cell contains the plasmid, it is safe because the anti-toxin is continually made keeping the toxin at bay. However, if a cell loses the plasmid during replication, the toxin hangs around even after the anti-toxin has been destroyed. Thus, all plasmid-free cells die ensuring survival of the plasmid in subsequent generations.
Because many pathogens carry antimicrobial resistance genes on plasmids, plasmid addiction systems may also be a vulnerable target for drug development. Scientists from The Rockefeller University found plasmid addiction systems in all 75 vancomycin-resistant enterococci isolates tested from patients in Illinois and Missouri. Plasmid addiction systems have also been found in other antibiotic resistant bacteria such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa.
How Can Plasmid Addiction Systems Be Targeted for Antimicrobial Development?
Targeting plasmid addiction systems for antimicrobial development is particularly appealing because it both eliminates the plasmid (and thus, antibiotic resistance genes) and treats the infection. Drugs can target plasmid addiction systems in several ways. For example, a drug can inhibit expression of the anti-toxin. This means that upon drug addition, the anti-toxin is no longer made and the remaining anti-toxin is quickly degraded leading to cell death. Alternatively, drugs can disrupt the interaction between the toxin and anti-toxin, also freeing the toxin to kill the cell.
Plasmid addiction systems may seem like selfish DNA whose sole purpose is to replicate itself regardless if it benefits the host or not. Once a bacterial cell becomes “infected” with a plasmid containing an addiction system, it is destined to keep that DNA perpetually.
