Scientists reveal new toxin that damages the gut

Scientists at La Trobe University have discovered how a diarrhea-causing strain of bacteria uses “molecular scissors” to cut open and destroy gut cells, leading to severe illness and sometimes death.

Published in Gut Microbes, the research reveals for the first time the three-dimensional structure of a toxin secreted by enteropathogenic E. coli (EPEC) bacteria, and shows how the bacteria use the toxin to invade and destroy the epithelial cells that line the gut.

The toxin, which is an enzyme called EspC, destroys the cells by cutting up their internal protein structure.

La Trobe University scientist Professor Begoña Heras, who co-led the research, said understanding how the dangerous bacterial toxin worked was critical for the future development of new, targeted drugs to treat EPEC infections in the face of rising antimicrobial resistance.

“Many strains of E. coli, including EPEC, which is a major cause of diarrheal disease, are becoming increasingly resistant to the antibiotics commonly used to treat these infections,” Professor Heras said.

“This is alarming as 1.3 million children under the age of 5 die each year from diarrheal illnesses due to the associated severe dehydration and loss of essential electrolytes.

“Revealing the structure of EPEC’s toxic weapon and showing how it destroys cells, brings us one step closer to stopping this deadly disease which affects millions worldwide.”

There are more than five types of E. coli that damage epithelial cells in different ways to cause gut infection.

These include STEC, which was responsible for the recent salad spinach recall and uses Shiga toxin to invade gut cells, and EPEC—the subject of this study—which uses the toxin EspC and is the leading cause of diarrhea in children and babies worldwide.

Currently, infections caused by the many diverse strains of E. coli are typically treated with broad-spectrum antibiotics. However, these drugs kill both harmful and beneficial gut bacteria, and E. coli’s rapid adaptation ability means these pathogens are becoming resistant to many antibiotics.

Dr. Jason Paxman, who co-led the research with Professor Heras, said treating E. coli infections had become increasingly difficult, with clinicians frequently needing to use strong antibiotics of last resort, meaning there are no other treatments available.

“We’re running out of options to treat bacterial diseases, with some bacterial pathogens now resistant to all antibiotics,” Dr. Paxman said.

“New antibiotics are still being developed, but the pace is extremely slow and when they become available, they’re often put in a stewardship and only used when absolutely necessary, as bacteria can develop resistance within just a few years.

“This is a huge issue, as most traditional antibiotics do not target specific bacteria—which means a single antibiotic can apply selective pressure across many bacterial species, whether it’s E. coli, Staphylococcus aureus and others, leading to widespread resistance to the one type of drug.”

Professor Heras, Dr. Paxman and the paper’s first author, Dr. Akila Pilapitiya worked with a multidisciplinary team of researchers at the La Trobe Institute of Molecular Science (LIMS) and La Trobe’s School of Agriculture, Biomedicine and Environment (SABE).

Dr. Pilapitiya, who worked on the research as a part of her Ph.D., said working with a multidisciplinary team was essential to understand how EPEC used EspC as a molecular weapon.

“It was already known that EPEC used EspC as a toxin, but little was known about its structure and how it worked,” Dr. Pilapitiya said.

“By using a multidisciplinary approach, I was able to determine the 3D structure of EspC toxin, which shows how it’s built and the role each of its parts play to make it work.

“This knowledge provides a foundation for designing new, more specific drugs that can disarm EPEC, combat diarrheal infections and protect our gut cells from damage.”

Professor Heras hopes the multidisciplinary approach can pave the way for other researchers to find new potential treatments for many harmful pathogens.

“Our work shows how combining different areas of science can help solve complex research questions and support the development of new drugs to protect human health,” Professor Heras said.

Professor Heras, Dr. Paxman and Dr. Pilapitiya are members of La Trobe’s School of Agriculture, Biomedicine and Environment (SABE) and the La Trobe Institute for Molecular Science (LIMS), where Professor Heras is co-lead of the Infection and Immunity Program.