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Utrecht scientists together with a global health-focused branch of pharmaceutical company GSK have found new and affordable molecules in the fight against diarrheal disease in young children. Shigella bacteria cause 165 million cases of diarrheal disease, including many fatalities, 70% of which are in children below the age of 5. More than 95% of these fatalities occur in the developing world. The outcome of the disease is more severe if it produces the shiga toxin, which can cause lethal kidney disease. In , the researchers present a new molecule that can block this toxin, which is increasing in prevalence among the four species of shigella bacteria.

Previous attempts by others yielded potent molecules capturing the toxin, but these molecules were too complex for further development and application in low-income countries. Furthermore, the toxin is a challenging target, as it moves from the intestinal tract to the circulation after a few days. While the present study focused on a strong capture in circulation, the Utrecht researchers also discovered a readily available polysaccharide and food additive that can capture the toxin in the intestines. Such a two-pronged approach may be required to fight this difficult pathogen.   

Developing countries

“We are very happy to have found a molecule that is not only effective, but also relatively easy and cheap to make”, says Roland Pieters, corresponding author of the publication. “That means it is very suitable for use in developing countries.” 

In order to capture the toxin the researchers explored glycodendrimers: tree-like molecules with appropriate carbohydrate leaves. Additionally, they studied a type of glycopolymer that assembles into a particle-like sphere of a similar size as the toxin. The latter particles were shown to be the most effective and studies indicated that they were non-toxic.

Ray of hope

Lluís Ballell, Head of the GSK Global Health Incubator, commented: “The effects of severe diarrhea are dramatic, particularly in children in the developing world. This innovation offers a ray of hope towards a simple and affordable solution that addressed the more pernicious effects of toxin secretion in diarrheal disease. We are very glad that both GSK and the Tres Cantos Open Lab Foundation were able to play an instrumental role in this project.”

This work is even more relevant since a strain of  E. coli strain (STEC) produces similar toxins for which no adequate therapy or vaccine is currently available. A recent STEC outbreak in Germany (2011) was responsible for 52 fatalities and thousands of severe infections.

Publication

Diksha Haksar*, Mostafa Asadpoor*, Torben Heise*, Jie Shi, Saskia Braber*, Gert Folkerts*, Lluis Ballell, Janneth Rodrigues, Roland Pieters*
Journal of Medicinal Chemistry, 29 April 2021, DOI 10.1021/acs.jmedchem.1c00152
* researchers affiliated with Utrecht ľ�ϸ���Ӱ��