Wednesday , August 4 2021

How does the structure of cytolysins influence their activity?



Imran Rahman (left) and Richard E. Heckart, professor of chemistry, Wilfred Van der Donk, lead author and member of Van der Donk’s laboratory. Credit: Jillian Nickel

Enterococcus faecalis is usually a harmless member of the bacterial community in the human gut, but it can also cause several infections, including liver damage. Bacteria produce cytolysin, a molecule that destroys cells. In a new study, researchers have shown how they do it.

Wilfred van der Donk (MMG), professor of chemistry and researcher at the Howard Hughes Medical Institute, said: “Cytolysin is an important molecule and has been known since the 1930s. Our laboratory determined the structure of cytolysin. only in 2013 ”.

It is worrying that E. Fecalis is resistant to vancomycin, which is used as a last resort to treat bacterial infections. By understanding how cytolysin affects cells, researchers want to prevent their production and reduce the number of deadly infections.

Cytolysin is made up of two subunits, CylLL “and CylLS”, which have previously been shown to kill cells in both mammals and bacteria. The structure of the subunit is stabilized with the help of a ring called a macrocycle. This ring staples the ends to prevent the structure from unfolding. To understand how they work, the researchers replaced each amino acid in these two subunits and decided which one. amino acid It is important.

“After the mutation of the amino acid residues, we purified and tested each variant to see if it had antibacterial activity or if it could lysate the rabbit’s blood cells,” said the lead author of the paper, a graduate student at the Van der Donk Institute. It’s Imran Rahman, he says. It turns out that the macrocycling of both subunits is important for both activities. “

In addition, researchers have found that “CylLL” contains an important hinge region. “The hinge contains three consecutive glycine residues and removing them makes CylLL very unstable and unclean,” says Rahman.

The residue helps CylLL to switch between two different shapes, a knife and an elongated shape that can cross the bacterial membrane. “When it lengthens, the subunits can pierce the membrane, so we think we need a glycine residue. Activity,” he said.

Researchers are interested in identifying cytolysin targets. “These molecules, unlike current antibiotics that bind to large cell targets, are small molecules. They seem to use them to pierce the membrane,” Vandeldonk said.

The study “Structure-activity relationship of enterococcal cytolysin” was published in SCA infection..


New insights into the pathogenic arsenal of common hospital pathogens


For more information:
Imran R. Rahman et al, Structure-activity relationship of enterococcal cytolysin, SCA infection (2021). DOI: 10.1021 / acsinfecdis.1c00197

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University of Illinois at Urbana-Champaign

Date: How does the structure of cytolysin affect its activity? (July 22, 2021) Retrieved July 22, 2021 at https://medicalxpress.com/news/2021-07-cytolysins.html

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