UIC researchers prove that drugs designed for bacteria have the potential to act on human cells.
According to researchers from the University of Illinois, Chicago, the antibiotics used to treat more common bacterial infections like pneumonia and sinusitis can also be used to treat human diseases like cancer. At least in theory.
As described in a new one Nature communication In a study, the team at the UIC College of Pharmacy demonstrated in laboratory experiments that eukaryotic ribosomes can be modified so that they respond to antibiotics in the same way as prokaryotic ribosomes.
Like humans, fungi, plants and animals are eukaryotes; They consist of cells with a well-defined nucleus. Bacteria, on the other hand, are prokaryotes. They are made up of cells that have no nucleus and have a different structure, size, and properties. The ribosomes of eukaryotic and prokaryotic cells, which are responsible for protein synthesis needed for cell growth and reproduction, are also different.
“Some antibiotics that are used to treat bacterial infections work in interesting ways. They bind to the ribosome of bacterial cells and very selectively inhibit protein synthesis. Some proteins are allowed to be made, but others are not, ”said Alexander Mankin, Alexander Neyfakh Professor of Medicinal Chemistry and Pharmacognosy at the UIC College of Pharmacy and lead author of the study. “Without these proteins, bacteria die.”
When people use antibiotics to treat an infection, the patient’s cells are not affected because the drugs are not designed to attach to the differently shaped ribosomes of eukaryotic cells.
“Because there are many human diseases that are caused by the expression of unwanted proteins – this is the case with many types of cancer or neurodegenerative diseases, for example – we wanted to know if it was possible to use an antibiotic to treat the A human cell will stop producing the unwanted proteins and only the unwanted proteins, ”Mankin said.
To answer this question, Mankin and the study’s first author, Maxim Svetlov, a research fellow at the Institute of Pharmaceutical Sciences, examined yeast, a eukaryote with cells that are similar to human cells.
The research team, which included partners from Germany and Switzerland, performed a “cool trick,” said Mankin. “We engineered the yeast ribosome to be more bacteria-like.”
Mankin and Svetlov’s team used biochemistry and fine engineering to modify a nucleotide greater than 7,000 in ribosomal yeast RNAwhich was enough to cause a macrolide antibiotic – a common class of antibiotics that works by binding to bacterial ribosomes – to act on the yeast ribosome. Using this yeast model, the researchers used genome profiles and high-resolution structural analysis to understand how each protein is synthesized in the cell and how the macrolide interacts with the yeast ribosome.
“Through this analysis, we understood that depending on a protein’s specific genetic signature – whether or not it has a ‘good’ or ‘bad’ sequence – the macrolide may or may not stop its production on the eukaryotic ribosome,” Mankin said. “This has conceptually shown us that antibiotics can be used to selectively inhibit protein synthesis in human cells and to treat human disorders caused by ‘bad’ proteins.”
The experiments of the UIC researchers provide a starting point for further studies. “Now that we know the concepts work, we can look for antibiotics that are able to bind in the unmodified eukaryotic ribosomes and optimize them to only block the proteins that are useful for a human are bad, “said Mankin.
Reference: “Context-specific effects of macrolide antibiotics on the eukaryotic ribosome” by Maxim S. Svetlov, Timm O. Koller, Sezen Meydan, Vaishnavi Shankar, Dorota Klepacki, Norbert Polacek, Nicholas R. Guydosh, Nora Vázquez-Laslop, Daniel N. Wilson and Alexander S. Mankin, May 14, 2021, Nature communication.
DOI: 10.1038 / s41467-021-23068-1
Other co-authors of the study are Dorota Klepacki and Nora Vázquez-Laslop from UIC; Timm Koller and Daniel Wilson from the University of Hamburg; Sezen Meydan and Nicholas Guydosh of the National Institutes of Health; and Norbert Polacek and Vaishnavi Shankar from the University of Bern.
This work was supported by grants from the National Health Institutes (R35 GM127134, DK075132, 1FI2GM137845), the German Research Fund (WI3285 / 6-1) and the Swiss National Fund (31003A_166527).