RNA Sequencing Finds New Drug Target for Deadly E.Coli Strain

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Recent advancements in RNA sequencing have illuminated a previously hidden molecular pathway that is a potential drug target for a fatal type of E.coli infection.

While most foodborne E.coli infections cause nausea, vomiting and/or diarrhea, there is a strain that can be fatal. Enterohermorrhagic E.coli (EHEC), mainly found in the feces of cows and sheep, releases Shiga toxins during infection, resulting in kidney and neurological damage. The newly discovered molecular pathway controls and reduces Shiga toxin production.

Contrary to most infections, antibiotics have been found to worsen EHEC by stimulating Shiga toxin production, leading to an increased risk of organ failure and death. But the new pathway, according to study author Jai Tree, a professor at the University of New South Wales (Australia), is not expected to be stimulated by antibiotics—an important findings since there are currently no commercially available treatments for EHEC.

Tree’s findings upend standard beliefs about pathways that control Shiga toxins. In 2001, researchers at Tufts and Harvard were the first to show how production of the Shiga toxin is controlled by a bacteriophage within the genome. For nearly two decades, this has been the only known pathway—until now.

"We have extended this work to show a new mechanism of toxin control that is, surprisingly, buried within the start of the DNA sequence that encodes the Shiga-toxin messenger RNA,” explained Tree, whose paper was recently published in PNAS. "We discovered a very short piece of the toxin messenger RNA is made into a regulatory non-coding RNA that silences the toxin and promotes growth of the pathogen."

Currently, patients who contract EHEC infections receive care to manage disease symptoms and reduce the effects of the toxin on the kidneys. The findings from Tree and his team open the door to new, direct treatments for EHEC.

“Our work shows a new mechanism for controlling toxin production that may be amenable to new RNA-based therapeutics to inhibit toxin production during an infection. We anticipate this would expand intervention options and potentially allow use of antibiotics that are currently not recommended since they stimulate Shiga toxin production,” Tree said.

EHEC outbreaks occur sporadically across the globe. The most significant recent outbreak was in Germany in 2011—more then 4,000 people were infected and 50 people died. The outbreak was linked to consumption of contaminated sprouts and in several cases, close contact with an infected person. A 1995 outbreak in South Australia infected 143 people, leaving 23 of them with permanent kidney and neurological damage. Children under five and older persons are at greatest risk of infection, and in Australia, that was the case. The most severe infections were seen in infants, some who died and others who required kidney transplants later in life.

While the study’s results are promising, Tree cautions that more research is needed to understand if the findings apply to a broad range of clinical EHEC isolates and to both types of Shiga toxins produced by human EHEC isolates. This research is currently underway.

“Our results identify a potential new target for the development of drugs that can suppress Shiga toxin production during EHEC infection. New treatments could therefore reduce the risk of kidney damage, neurological complications and death. We look forward to testing these new interventions in the next stage of our research,” Tree concluded.

Photo: An abstract depiction of the Shiga toxin bacteriophage with a red genome. Credit: UNSW Sydney.