As the search continues for new antibiotics to treat drug-resistant infections, a group of researchers used the Canadian Light Source (CLS) at the University of Saskatchewan to address the problem from a different direction, by trying to weaken the ability of bacteria to develop resistance in the first place.
“The goal is to knock the bacterial cells down in terms of their resistance,” said Dr. Anthony Clarke, Professor and Dean of Science at Wilfrid Laurier University and adjunct professor at the University of Guelph. “We haven’t been successful over the last 30 years in finding new classes of antibiotics so, in the short term, we’re trying to weaken the cells so our own immune system can take over to fight infection.”
The target for his team’s work is peptidoglycan, which gives bacterial cell walls their rigidity. “Think of it as building a brick wall around the bacteria’s cells,” said Clarke. Since peptidoglycan can be broken down by lysozyme, an enzyme that exists in human immune systems, bacteria have developed strategies that block these enzymes by modifying their peptidoglycan, thereby “cementing the bricks in place,” and resisting our defences.
In the search for compounds that will stop the enzyme from modifying peptidoglycan (and helping pathogenic bacteria survive), Clarke and his colleagues used the CMCF beamline at the CLS to study one particular enzyme of Staphylococcus aureus, a bacterium that causes a wide variety of diseases in humans and animals (eg., MRSA).
“To try to develop compounds that inhibit the enzyme, you need to know what that structure looks like at an atomic level. You need to see the compound inside the structure, where it binds. Then, you can use chemistry to modify the compound to make it bind tighter and enhance its overall effect,” he explained. The objective is not necessarily to kill the cell, he said, but rather to find inhibitors that make the cell more susceptible to our immune defenses.
The research, recently published in The Journal of Biological Chemistry, is foundational science that could guide the development of new antibacterial drugs, said Clarke, who has been studying enzyme systems for more than three decades. “It’s a lot of hard work and very few eureka moments, and it’s always a challenge to stay ahead of bacteria, but I’m optimistic. With the knowledge we’ve been gaining, the technologies available to us and the talent of young scientists who understand the importance of basic research, I know we’ll carry on the fight.”
Jones, Carys S., David Sychantha, P. Lynne Howell, and Anthony J. Clarke. "Structural basis for the O-acetyltransferase function of the extracytoplasmic domain of OatA from Staphylococcus aureus." Journal of Biological Chemistry 295, no. 24 (2020): 8204-8213. DOI: 10.1074/jbc.RA120.013108.
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