Team develops promising new form of antibiotic that causes bacterial cells to self-destruct
To address the global threat of antibiotic resistance, scientists are exploring new ways to bypass bacterial cell defense systems. Researchers at the University of Toronto (U of T) have used what they learned from previous research on cancer to develop a new compound that causes bacterial cells to self-destruct.
The research team’s results will be published in the Journal of Medicinal Chemistry.
This new form of antibiotic targets a naturally occurring enzyme (caseinolytic protease proteolytic subunit, or ClpP) that chews up old or defective proteins and plays an important role in cellular housekeeping. It is designed to. This new compound causes the ClpP enzyme to go into overdrive, so it starts chewing up proteins that shouldn’t be digested, ultimately killing your own cells from the inside out.
“Most antibiotics inhibit the process,” says Dr. Walid A. Awly, a professor of biochemistry at the University of Toronto. “This approach allows for the development of this new class of compounds that dysregulate processes and that we hope will eventually find their way into clinical practice,” said Awry, co-author of Robert Battey, Ph.D. We built on previous research in this area by working closely with colleagues and colleagues.
“We found that (the enzyme) that is present in cancer cells is also present in bacteria. The difficult part of this project was finding a way to attack bacterial ClpP rather than human ClpP,” Houry said. added.
With the Canada Light Source (CLS) at the University of Saskatchewan’s (USask) CMCF beamline, Houry’s team visualized the structural differences between human and bacterial ClpP and how these new compounds behave when attacking ClpP. I was able to understand. The group took advantage of subtle structural differences between human and bacterial enzymes to design compounds that could target harmful bacteria without damaging human cells along the way.
Houry says this new approach to antibiotics has great potential for treating bacterial infections such as meningitis and gonorrhea.
Further information: Funing Lin et al, Structure-Based Design and Development of Phosphine Oxides as a Novel Chemotype for Antibiotics that Dysregulate Bacterial ClpP Proteases, Journal of Medicinal Chemistry (2024). DOI: 10.1021/acs.jmedchem.4c00773
Provided by Canadian Light Source
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