Natural plasmid incompatibility could help combat antibiotic resistance
One major factor underlying antibiotic resistance is that bacterial cells commonly transfer circular sections of DNA, known as plasmids, between each other. These plasmids, which can replicate independently of the bacteria that house them, often contain genes coding for proteins that confer antibiotic resistance, such as efflux pumps, and these genes can disperse around many different populations and species of bacteria.
If there was a way that these plasmids could be destroyed, the bacteria that possessed them would once again become susceptible to antibiotics. To do this, the team of chemists, led by Paul Hergenrother, took inspiration from a natural process known as plasmid incompatibility. ’If there is one plasmid in a cell and another one is introduced, then they compete with each other for resources,’ explains Hergenrother. ’One of them wins and the other is eliminated’.
The mechanism behind plasmid incompatibility involves a small section of RNA produced by one plasmid binding to the RNA produced by another plasmid, thereby preventing it from synthesising an enzyme that it needs in order to replicate. Hergenrother and his team decided to look for a synthetic molecule that would perform the same function.
They focused their search on aminoglycosides, which bind tightly to RNA, and eventually settled on the aminoglycoside antibiotic apramycin. They tested apramycin’s plasmid-destroying abilities on a strain of Escherichia coli harbouring a plasmid termed pMU2403, which possesses a gene that confers resistance to the antibiotic ampicillin . In bacteria grown in the presence of 18 ?g/mL of apramycin, the researchers discovered that the pMU2403 plasmid was eliminated in practically 100 per cent of the E. coli cells after 250 generations. These cells were then susceptible to ampicillin.
Hergenrother and his team are now carrying out further research to determine whether apramycin is effective against plasmids in other strains of antibiotic-resistant bacteria.
J C B DeNap et al., J. Am. Chem. Soc., 2004, 126, 15402