Bacteria are evolving in their abilities to be resistant to antibiotic treatments. This is creating havoc for the health industry as antibiotic-resistant bacteria can spread and infect other people more easily. Bacteria are able to acquire antibiotic resistance through beneficial mutations, or changes to their DNA sequences, that allow them to survive and continue replicating. A research team from the Baylor College of Medicine has investigated the mechanism by which antibiotics are able to create new mutations in bacteria, which can then lead to antibiotic resistance.
The teams’ experiments mainly focused on the antibiotic, ciprofloxacin (Cipro), which stops the growth of bacteria. Cipro targets proteins that are involved in the replication of DNA, leading to the inhibition of bacterial replication and division. Applying this drug to E. coli in culture led to an increase in the production of reactive oxygen species (ROS) in the cells, ranging from 15-20% more. ROS are extremely reactive and damaging compounds, and there are numerous ways by which they can be produced. An increase in ROS not only generates cellular stress from an increase in toxicity but can also damage DNA. The research team found that the increase in ROS caused double-stranded breaks in DNA, which are commonly fixed using error-prone repair mechanisms like non-homologous end joining. With this repair mechanism, each end of a broken strand is bound by proteins, then DNA nucleotides are removed in order to create overhangs that can allow for the two strands to be fused back together. This leads to the introduction of mutations as portions of the DNA sequence are removed, enabling bacteria to develop antibiotic resistance.
Image source: Rodolfo Parulan Jr
In order to further examine this new mechanism, the research team used edaravone, a drug that helps limit cellular stress by reducing ROS levels in the cells. Application of this drug decreased the increased stress associated with Cipro treatment and limited the introduction of new mutations. Essentially, edaravone is able to inhibit the cell-specific side effects of antibiotics without impairing the ability of the antibiotics to kill the bacteria.
These findings are relevant to current medical issues as edaravone can help limit the spread of bacterial resistance by limiting the introduction of new mutations that can then translate to bacterial resistance. While bacteria continue to evolve, the rate of research on new drugs and antibiotics to fight them has been lagging. Therefore, these findings have a direct clinical application.
Featured Image Source: Steve Buissinne
