UNIVERSITY PARK, Pa. -- Compounds that stop a cellular rescue operation for stuck ribosomes may bolster the nation's defenses against biowarfare and bioterrorism, as well as create alternative antibiotics to handle increasingly resistant pathogens, according to a team of researchers.
In a study of macrophages -- white blood cells -- from animals, researchers used two inhibitors -- KKL-10 and KKL-40 -- to stop the proliferation of Franscisella tularensis, bacteria that the U.S. Centers for Disease Control classifies as a tier 1 select agent because the strain is highly infective and easily spread, said Kenneth Keiler, professor of biochemistry and molecular biology, Penn State.
The compounds target ribosomes in the translation phase of the bacteria's genetic process, he added. For bacteria to grow and proliferate, protein-generating ribosomes, like engines rolling down a track, must travel down the messenger RNA (mRNA) to translate additional proteins. However, when the ribosomes become stuck, the bacteria dispatches ribosome rescue factors -- tmRNA, ArfA and ArfB -- to free the ribosome.
Keiler said that KKL-10 and KKL-40 were able to halt this rescue operation in the bacteria without damaging host cells.
"At the beginning of the study, we identified compounds that block rescue of ribosomes that are stuck on mRNA, and these have antibiotic activity against a number of pathogens that we can test in the lab," said Keiler. "In this study, first, we wanted to test the compounds against a pathogen that is important for biodefense and we also wanted to make sure that these compounds would work inside eukaryotic cells."