Tag: compounds

New compounds to combat antibiotic resistance

New compounds to combat antibiotic resistance

To address the global threat of antibiotic resistance, scientists are on the hunt for new ways to sneak past a bacterial cell’s defence system. Taking what they learned from a previous study on cancer, researchers from the University of Toronto (U of T) have developed novel compounds that trigger bacterial cells to self-destruct.

The new form of antibiotics is designed to target a naturally occurring enzyme — caseinolytic protease proteolytic subunit, ClpP, for short — which chews up old or defective proteins and plays an essential role in cellular housekeeping. The new compound kicks the ClpP enzyme into overdrive, so it begins chewing up proteins that it is not supposed to, eventually killing its own cell from the inside out. Video: New compounds to combat antibiotic resistance

“Most antibiotics inhibit a process,” says Dr. Walid A. Houry, professor of biochemistry at the University of Toronto. “With this approach, we are dysregulating a process, and this allows us to develop this new class of compounds that we eventually hope to get into a clinic.” Houry worked closely with Dr. Robert Batey and colleagues to build upon their previous work in this area.

“It turns out that the [enzyme] present in cancer cells is also present in bacteria. For this project, the tricky thing was trying to find a way to hit the bacterial ClpP, but not the human ClpP.” Houry said.

Read more on CLS website

Attacking cancer cells from the inside out

Attacking cancer cells from the inside out

Researchers from the University of Toronto (U of T) are harnessing the power of proteins to stop cancer cells in their tracks.

“Proteins are the workhorses of the cell,” said Walid A. Houry, professor of biochemistry at U of T. “They define the cell and allow it to divide or migrate if needed.”

The team is especially interested in proteases, enzymes that chew up old or misfolded proteins and act as cellular quality control. Houry and his colleagues used the CMCF beamline at the Canadian Light Source (CLS) at the University of Saskatchewan to identify key compounds affecting these quality control mechanisms that cause cell dysfunction and, ultimately, cell death. Their research paper was recently published in Structure.

“Let’s say you have a small puppy and when you leave it in the room, it starts chewing your sofa, your carpet; it’s just hyper and eating everything up,” Houry said. The compounds cause the proteases to act like the puppy, “and the cell cannot handle this type of disruption to its machinery.”

By targeting the cell’s self-destruct button, Houry’s team, including collaborators at Madera Therapeutics, is designing a new approach to cancer therapy. Synchrotron techniques allowed the researchers to visualize the interaction between their compounds and the proteases.

Houry said hard-to-treat cancers like glioblastomas and certain types of breast cancers are good candidates for this new approach.

“Instead of inhibiting a protease, we are hyperactivating the protease, and that is unique.”

The CLS is crucial to the team’s work.

“Synchrotron technology is extremely important for us and our structure-based drug design,” he said. “We want to know why the protein is going wild when we add our compound.”

Read more on the CLS website

Image: Houry research team