Credit: Journal of Medicinal Chemistry (2024). DOI: 10.1021/acs.jmedchem.4c00773
To address the global threat of antibiotic resistance, scientists are looking for new ways to circumvent the defense system of bacterial cells. Building on what they learned from a previous cancer study, researchers at the University of Toronto (U of T) developed new compounds that trigger bacterial cells to self-destruct.
The team’s results appear in the Journal of Medicinal Chemistry.
The new form of antibiotics is designed to target a naturally occurring enzyme — the proteolytic subunit of caseinolytic protease, ClpP, for short — that destroys old or defective proteins and plays a critical role in cellular maintenance. The new compound gives the ClpP enzyme a boost, so it starts chewing up proteins it’s not supposed to, ultimately killing its own cell from the inside.
“Most antibiotics inhibit a process,” says Dr. Walid A. Houry, professor of biochemistry at the University of Toronto. “With this approach, we deregulate a process, which allows us to develop this new class of compounds that we hope to eventually bring to the clinic.” Houry worked closely with Dr. Robert Batey and his colleagues to build on their previous work in this area.
“It turns out that (the enzyme) found in cancer cells is also found in bacteria. For this project, the challenge was trying to find a way to reach bacterial ClpP, but not human ClpP.” , adds Houry.
The Canadian Light Source (CLS) at the CMCF beamlines at the University of Saskatchewan (USask) allowed Houry’s team to visualize the structural differences between human and bacterial ClpP and understand how their new compounds behaved when they attacked the ClpP. The group capitalized on minor structural differences between human and bacterial enzymes to design compounds that could target harmful bacteria without damaging human cells in the process.
According to Houry, this new approach to antibiotics has great potential for treating bacterial infections such as meningitis and gonorrhea.
More information:
Funing Lin et al, Structure-based design and development of phosphine oxides as a new chemotype for antibiotics that deregulate bacterial ClpP proteases, Journal of Medicinal Chemistry (2024). DOI: 10.1021/acs.jmedchem.4c00773
Provided by Canadian Light Source
Quote: A team develops a promising new form of antibiotic that causes bacterial cells to self-destruct (October 18, 2024) retrieved October 18, 2024 from
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