Drugs

Avoiding The Superbug Apocalypse: New Antibiotic Being Developed Would Battle TB, Anthrax, And Food Poisoning

New Target For Antibiotics Discovered
Researchers out of Penn State have a candidate drug that is more effective than current treatments in killing antibiotic-resistant bacteria. sparktography Flickr Creative

We keep on hearing about the impending apocalypse of antibiotic-resistant bacteria, the so-called "superbugs," that will render all last-line defense antibiotics useless. But here's some good news: a new class of antibiotics is being developed by Professor Kenneth Keiler at Penn State University to target bacteria in a completely new way. Describing the new chemical in the current issue of the journal Proceedings of the National Academy of Sciences, Keiler and his team suggested that we may have a new weapon against drug-resistant strains of tuberculosis, anthrax, and Shigella, a bacterium that causes foodborne illness.

The antibiotic targets a pathway in bacteria that Keiler discovered as a graduate student in 1996, which is important in protein creation in bacteria. The process called "trans-translation" helps bacteria to keep protein synthesis moving by removing faulty messenger RNA. By using a pharmaceutical chemical to use this system to gum up the works in bacterial production, tough-to-treat bacteria can be killed easily. The process does not exist in plants, animals, or humans, so a specifically-targeted chemical would not have significant effects on a person's cells. "The idea is that if we can disturb trans-translation -- bacteria's quality-control step -- then we can throw a wrench into the protein-synthesis assembly line and prevent the organisms from making copies of themselves," Keiler said.

To find a molecule that could specifically block this pathway, Keiler's lab utilized high-throughput screening of pharmaceutical compounds. This method screens thousands of chemicals very quickly in parallel to see if they can affect the growth of bacteria. "Our team tested about 663,000 different molecules," Keiler said. "Specifically, we tested the molecules against a strain of E. coli and monitored how they were affecting the organism's trans-translation process." By the time they completed this stem, they had whittled over half a million candidate chemicals down to only 46 that disrupted the "trans-translation" process in bacteria.

Further testing of the chemicals in infectious bacteria, such as Shigella, which is a large source of food-borne illness, and Bacillus anthracis, or anthrax, showed that only one molecule called KKL-35 was able to block the growth of distantly-related bacteria, making it "broad-spectrum." The tests showed that KKL-35 specifically blocked the trans-translation process. The research team then investigated the potency of the drug on the bacteria that causes tuberculosis, Mycobacterium tuberculosis, which is becoming drug-resistant in many countries around the globe. The drug was more than 100-fold better at blocking bacterial growth than the currently used treatments.

Because quick evolution and mutation of bacteria can lead to drug resistance, the researchers tested mutated variant strains of bacteria to see if they would be susceptible to KKL-35. "In our laboratory experiments, we found no mutant strains that were resistant to KKL-35," Keiler said. "One possible explanation for the lack of resistant mutants in lab experiments is that changes in trans-translation molecules that disrupt drug binding also eliminate trans-translation activity. Resistant mutants probably would evolve eventually, but at least it looks like it will be very difficult. That means resistant mutants might be slow to arise and spread."

New antibiotics are desperately needed, and the Infectious Diseases Society of America has petitioned Congress for increased funding for antibiotics development. It has also initiated the 10x20 program, which aims to encourage 10 new antibiotics to be approved by the Food and Drug Administration by 2020. Since the initiation of the program, only one drug was approved in 2009.

Safety tests and pursuit of animal and human trials are sure to follow.

 

Source: Ramadoss N, Alumasa J, Cheng L, et al. Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity. PNAS. 2013

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