New ribosome-targeted antibiotics act against drug-resistant bacteria

A new study published in Nature reports on a new antibiotic that binds to the ribosomes of bacterial cells and prevents drug-resistant pathogens from causing disease in mice.

The study, co-authored by researchers at the University of Illinois at Chicago, not only shows the potential of a drug called iboxamycin to help people who are sick due to antibiotic-resistant bacteria, but also the drug It also identifies the most overcoming methods. Extensive mechanisms of resistance to this class of antibiotics.

This drug — a new class of antibacterial drug, synthetic oxepanoproline amide — was developed by a research co-author at Harvard University and tested in animals.

Nature research, “Synthetic antibiotic class that overcomes bacterial multidrug resistanceReported that Ivoxamycin was potently effective in combating both Gram-negative and Gram-positive drug-resistant bacteria in mouse models.

The study also reports on the discovery of UIC. This is the molecular mechanism that allows the drug to overcome resistance. This is important information that the scientific community can use to make more informed decisions when searching for and developing new antibiotics and designing studies to test them.

“It was exciting to see this drug bind to the structure of drug-resistant ribosomes. The drug binds just like a normal ribosome, but a rearrangement of an important structure that has never been observed. It was very surprising to cause the study. Co-author of the study, Yuri Polykanov, an associate professor of biological sciences at the University of Liberal Arts and Sciences and an associate professor of pharmacy at the Faculty of Pharmacy, said: Stated.

In a previous study, Polykanov developed a unique approach for visualizing ribosomes that are resistant to traditional antibiotics. Through this process, he and Alexander Mankin, a professor of pharmaceutical science at UIC, Reported at Nature Chemical Biology in January Methylation, the process of altering the chemical composition of nucleotides in the drug binding sites of ribosomes, prevents such ribosomes from binding to some clinically important antibiotics, making them drug resistant. The paper.

To understand how and why Ivoxamycin overcomes resistance, Polykanov and UIC graduate student co-lead author Egor Syroegin applied a unique visualization technique. UIC researchers co-crystallized the bacterial ribosome with the drug and frozen the crystals. Next, intense X-rays were used at the Argonne National Laboratory’s Advanced Photon Source facility to identify the diffraction pattern of the molecule, where the radiation hit the atoms in the crystal and bounced off. This pattern was used to calculate electron density maps of the ribosome-drug complex and visualize their interactions.

“The whole process of atomic structure determination using X-rays is like a 3D puzzle,” says Polykanov. “We needed to identify a vacant lot in the ribosome puzzle and find the right drug. Doing so allowed us to see where and how the drug bound to the ribosome.”

When UIC researchers examined the visualization of Harvard drugs that interact with drug-resistant ribosomes, they found something unexpected.

“We also found that the most common resistance mechanism through ribosome methylation does not work for this new drug because it binds to methylated ribosomes and avoids this type of resistance. We have found that iboxamycin actually moves the methylated nucleotides at the center of the ribosome and the drug binding site out of the way of the drug, allowing both the drug and the methylated nucleotides of the drug-resistant ribosome to coexist — This was totally unexpected and unprecedented, “said Polykanov.

“This shows that Mother Nature is much smarter than us. There is certainly a place for rational drug design, but we can’t forget the importance of simple trial and error,” he says. I did. “Neither the activity spectrum of iboxamycin nor its efficacy in resistant strains could be predicted from prior knowledge.”

Additional UIC co-authors for this study include Mankin and Dorota Klepacki.

Andrew Myers, a professor of chemistry and chemical biology, co-authors of the study, Matthew Mitchelltree, Amana Spicipati, Catherine Sylvestre, Jeremy Mason, Danielter Williger, Jambatista Testrin, Aditya Pote, Kelvin Wu, He led a research team at Harvard University, including Richard Porter Radley. Kelly Chatman.

Research at UIC was supported by grants from the Illinois Startup Foundation and the National Institutes of Health (R21AI137584, R01GM132302, R35GM127134). Additional funding for research and disclosure can be found in the paper.