Treating disease by preventing the responsible bacteria from replicating may lead to a more-effective kind of antibiotic that does not lead to drug resistance, according to researchers at Penn State University whose work in the current issue of the journal Proceedings of the National Academy of Sciences may result in a new type of treatment for tuberculosis and other diseases.
Researchers described 46 previously untested molecules that target and disrupt an important step in the process of protein synthesis in bacteria called “trans-translation.” This interruption renders the bacteria incapable of replicating.
“If you imagine the bacterial protein-synthesis pathway as a factory assembly line, trans-translation is responsible for keeping the assembly line moving. Faulty messenger RNA (mRNA) — which is RNA that conveys genetic information from DNA to proteins — can block the synthesis machinery. Trans-translation removes these blocks from the assembly line, thereby keeping the system running smoothly,” said Kenneth Keiler, an associate professor of biochemistry and molecular biology at Penn State University.
“Were it not for trans-translation, all the subsequent steps in the factory assembly line would get held up and the organism would not be able to function properly — synthesizing the proteins that it needs for survival.”
Therefore, if it were possible to disturb trans-translation, the protein-synthesis “assembly line” would be interrupted and the organisms wouldn’t be able to replicate, Keiler noted.
For the study, investigators tested about 663,000 different molecules against a strain of E. coli and monitored how they were affecting the organism’s trans-translation process. They identified 46 different molecules that appeared to be effective in the disruption of trans-translation.
They then tested these molecules’ efficacy at disturbing trans-translation in other bacteria that are known to cause illness: Shigella, Bacillus anthracis and Mycobacterium tuberculosis. Of the 46 molecules, one called KKL-35 seems to be the most promising.
“We found that [KKL-35] inhibits the growth of very distantly related bacteria, and this suggests that it may have antibiotic activity against a very broad spectrum of species,” said Keiler. “As for Shigella and Bacillus anthracis, we were able to show that, in the presence of KKL-35, the cells died specifically because the molecule halted the trans-translation process.”
The team found that, compared with currently used tuberculosis drug therapies, the KKL-35 molecule was 100-fold more effective at inhibiting the growth of the bacterium. They also noted that, in their laboratory experiments, there were no mutant strains resistant to KKL-35.
