Stopping Ribosome Rescue May Help Combat Virulent Bacteria

Two new inhibitory compounds—named KKL-10 and KKL-40—could hold the key to preventing the proliferation of the highly virulent bacterium Francisella tularensis, according to a recent study.

Tyler D. P. Goralksi, Penn State University, University Park, Pennsylvania, and colleagues published the results of their study in Antimicrobial Agents and Chemotherapy.

In cells, proteins are synthesized by the ribosome, by a process called translation, after decoding of the genetic information. During translation, ribosomes can sometimes become stalled at the end of the messenger RNA (mRNA) molecule—if the mRNA is defective, for instance. Indeed, most antibiotics work by inhibiting microbial protein synthesis by stalling ribosomes in this way.

Ribosomes that become trapped on mRNA must therefore be rescued for productive cycles of cellular protein synthesis to occur. And many bacteria have developed rescue pathways that allow them to overcome antibiotic mechanisms and thereby add to the rising problem of antibiotic resistance.

Most bacteria use a mechanism known as trans-translation to rescue trapped ribosomes, and some also use other mechanisms that are mediated either by the alternative ribosome-rescue factor A (ArfA) or ArfB.

As a consequence, the authors emphasize that “[r]ibosome rescue pathways are potential targets for new antibiotics because they are required for virulence or viability in many pathogenic species.”

With this in mind, Goralski and colleagues conducted a study to identify compounds that can inhibit the rescue of trapped ribosomes and potentially stop the proliferation of highly pathogenic organisms such as Franscisella tularensis, the causative agent of tularemia, a potentially serious illness that occurs naturally in the United States.

F. tularensis is classified by the Centers for Disease Control and Prevention (CDC) as a Tier 1 select agent, on the basis of its high infectivity and ease of spread, and therefore its ability to pose a significant threat to public health and safety. Pneumonic tularemia has a 60% mortality rate if left untreated. “F. tularensis strains resistant to multiple antibiotics are a biowarfare threat,” the authors write. “In the absence of an effective vaccine, new antibiotic targets and compounds are needed to ensure biodefense.”

The researchers discovered that 2 oxadiazole inhibitors, KKL-10 and KKL-40, were able to prevent growth of F. tularensis in liquid culture and during ex vivo infection of eukaryotic cells. These compounds targeted ribosomes during translation and stopped ribosome rescue, but were not toxic to eukaryotic cells in culture. The team also showed that ribosome rescue is required for F. tularensis growth at all stages of its infection cycle.

“Because KKL-40 and KKL-10 have little structural resemblance to other antibiotics and target ribosome rescue, a pathway that is not targeted by other antibiotics, cross-resistance is unlikely to be a problem,” the authors note.

“Overall, these results encourage further development of KKL-40 and KKL-10 as antibiotics for therapeutic use against F. tularensis and other intracellular pathogens, particularly for strains that are resistant to existing drugs,” they conclude.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals, and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.