UIC researchers are proving that drugs designed for bacteria have the potential to act on human cells.
Antibiotics used to treat common bacterial infections, like pneumonia and sinusitis, can also be used to treat human illnesses, like cancer, according to researchers at the University of Illinois at Chicago. Theoretically, at least.
As shown in a new Nature Communication study, the UIC College of Pharmacy team showed in laboratory experiments that eukaryotic ribosomes can be modified to respond to antibiotics in the same way as prokaryotic ribosomes.
Fungi, plants, and animals, like humans, are eukaryotes; they are made up of cells with a clearly defined nucleus. Bacteria, on the other hand, are prokaryotes. They are made up of cells that do not have a nucleus and have different structure, size and properties. The ribosomes of eukaryotic and prokaryotic cells, which are responsible for synthesizing proteins necessary for cell growth and reproduction, are also different.
âSome antibiotics, 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, âsaid Alexander Mankin, Alexander Neyfakh professor of medicinal chemistry and pharmacognosy at UIC College of Pharmacy and lead author of the study. âWithout 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 bind to ribosomes of different shapes than eukaryotic cells.
“Because there are many human diseases caused by the expression of unwanted proteins – this is common in many types of cancer or neurodegenerative diseases, for example – we wanted to know if it would be possible to use an antibiotic. to prevent a human cell from making the unwanted proteins, and only the unwanted proteins, âMankin said.
To answer this question, Mankin and the study’s first author, Maxim Svetlov, an assistant research professor in the Department of Pharmaceutical Sciences, turned to yeast, a eukaryote with cells similar to human cells.
The research team, which included partners from Germany and Switzerland, did a “cool thing,” Mankin said. “We designed the yeast ribosome to look more like bacteria.”
Mankin and Svetlov’s team used biochemistry and fine genetics to modify over 7,000 nucleotides in ribosomal yeast RNA, which was enough for a macrolide antibiotic – a common class of antibiotics that work by binding to bacterial ribosomes – to act on the yeast ribosome. Using this yeast model, the researchers applied genomic profiling and high-resolution structural analysis to understand how each protein in the cell is synthesized and how the macrolide interacts with the yeast ribosome.
“Thanks to this analysis, we understood that depending on the specific genetic signature of a protein – the presence of a” good “or” bad “sequence – the macrolide can stop its production on the eukaryotic ribosome. or not, âMankin said. “This has shown us, conceptually, that antibiotics can be used to selectively inhibit protein synthesis in human cells and used to treat human disorders caused by ‘bad’ proteins.”
The experiments of UIC researchers constitute a platform for future studies. âNow that we know the concepts work, we can look for antibiotics that can bind to unmodified eukaryotic ribosomes and optimize them to only inhibit proteins that are bad for a human,â Mankin said.
Reference: âContext-specific action of macrolide antibiotics on the eukaryotic ribosomeâ by Maxim S. Svetlov, Timm O. Koller, Sezen Meydan, Vaishnavi Shankar, Dorota Klepacki, Norbert Polacek, Nicholas R. Guydosh, Nora VÃ¡zquez-Laslop, Daniel N Wilson and Alexander S. Mankin, May 14, 2021, Natural communications.
DOI: 10.1038 / s41467-021-23068-1
Additional study co-authors are Dorota Klepacki and Nora VÃ¡zquez-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 University of Bern.
This work was supported by grants from the National Institutes of Health (R35 GM127134, DK075132, 1FI2GM137845), the German Research Foundation (WI3285 / 6-1) and the Swiss National Science Foundation (31003A_166527).