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March 17, 2016

Halting Ribosomal Rescue Key to Thwarting Virulent Bacteria

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    Scanning electron micrograph of a murine macrophage infected with Francisella tularensis strain LVS. Macrophages were dry-fractured by touching the cell surface with cellophane tape after critical point drying to reveal intracellular bacteria. Bacteria (colorized in blue) are located either in the cytosol or within a membrane-bound vacuole. [NIAID]

    The general mechanism for most antibiotics is stopping microbial protein translation by stalling ribosomes on mRNA molecules. However, many bacteria have evolved rescue pathways that allow them to circumvent antibiotic mechanisms, helping to facilitate the rapid increase in drug resistance. Yet now, researchers at Penn State University have released results from a new study that describes the use of two inhibitory compounds to stop the proliferation of the extremely virulent bacteria Francisella tularensis, the cause of the disease tularemia.

    The new compounds target ribosomes in the translation phase of the bacteria's genetic process. For bacteria to grow and proliferate, protein-generating ribosomes must travel along mRNA to translate the genetic code into proteins. However, when the ribosomes become stuck, the bacteria quickly dispatches ribosomal rescue factors—tmRNA, ArfA, and ArfB—to free the ribosome. The researchers found that the new compounds—named KKL-10 and KKL-40—were able to halt the 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," explained co-senior author Kenneth Keiler, Ph.D., professor of biochemistry and molecular biology and Penn State University. "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."

    The findings from this study were published recently in Antimicrobial Agents and Chemotherapy in an article entitled “Inhibitors of Ribosome Rescue Arrest Growth of Francisella tularensis at All Stages of Intracellular Replication.”

    Tularemia can cause fatalities in up to 60% of the cases if left untreated, and unfortunately it has been stockpiled as a biowarfare agent during the Cold War.

    "In today's world of terrorism, it is essential that we are well-prepared to defend ourselves and our military personnel against biowarfare agents," noted co-senior study author Girish Kirimanjeswara, Ph.D., assistant professor of veterinary and biomedical sciences at Penn State University. "In that regard, finding new targets and antibiotics against these agents is critical, and our research shows that these compounds may be very."

    Continued use of antibiotics to kill pathogens has led to an increasing number of diseases to become resistant to conventional drugs and treatments. This has increased the urgency to find new medicines and new ways of stopping pathogens.

    "There are many pathogens that are resistant to all existing antibiotics—if you are infected with one of these totally resistant strains and show up in the clinic there's nothing the doctors can do for you," remarked Dr. Keiler. "If your immune system can fight off the infection, you'll survive and if it can't, you die. It's back to pre-1940s-era medicine. If we don't develop new drugs, and the resistant genes are going to continue to spread, more and more diseases will become untreatable."

    The investigators hypothesize that the use of these new compounds and targeting a new pathway many pathogens may struggle to adapt resistance to the treatment.

    "One of the good things about our compounds is this is a new chemical, so it's unrelated to any of the existing drugs, which means maybe there may not be enzymes out there to modify those drugs and inactivate them," Dr. Keiler stated. "Although we won't know that until we get into the clinic."

    "This strategy allows bacteria to survive and escape from host immune responses, for example, within the host cells, and there are not many antibiotics that can target a bacterium in all these compartments," Dr. Kirimanjeswara added. "In that regard, these compounds were effective outside the cells, in the various stages of endocytic vesicles, and in the cytoplasm, making it a very attractive way to treat bacterial diseases."

    The research group is currently looking to take the next steps and test their compounds in animals affected with tularemia and other microbial infections. 

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