The anticonvulsant drug lamotrigine appears to hinder the assembly of bacterial ribosomes, and may therefore play a role in the development of a new class of antibiotics, according to recent findings.
In the study, researchers evaluated a variety of chemicals, among them previously approved drugs and compounds known to have bioactivity. They tested these chemicals on a model bacterium, Escherichia coli, to determine their ability to induce cold-sensitive growth inhibition, due to the association of cold-sensitive phenotypes with genetic defects in ribosome assembly seen in previous data.
The researchers found that lamotrigine (Lamictal, GlaxoSmithKline) yielded an extremely cold-sensitive growth phenotype, and also resulted in the accumulation of immature ribosomal subunits at 15 degrees Celsius.
Additional analysis found that a significant accumulation of these non-native particles occurred after only 5 minutes of treatment of E. Coli with 2x MIC of lamotrigine. The particles were found to be immature 30S and 50S ribosomal subunits. According to the researchers, this was not the result of translation inhibition because lamotrigine is “incapable of perturbing protein synthesis in vivo or in vitro.” Additionally, the researchers were able to identify the precise target for lamotrigine, which is domain II of initiation factor IF2. This suggests that IF2 plays a role in ribosome assembly.
According to the researchers, these findings may herald a new class of antibiotics to which bacteria have not yet developed resistance.
"Ribosome-inhibiting antibiotics have been routinely used for more than 50 years to treat bacterial infections, but inhibitors of bacterial ribosome assembly have waited to be discovered," study researcher Eric D. Brown, PhD, professor of biochemistry and biomedical sciences at McMaster University, in a press release. "Such molecules would be an entirely new class of antibiotics, which would get around antibiotic resistance of many bacteria. We found lamotrigine works."
Disclosure: The researchers report no relevant disclosures.