Protein finding could pave way for new antibiotics

Antibiotics revolutionized healthcare when they were introduced in the early twentieth century, making many severe and often fatal diseases easily treatable. But bacteria began developing resistance to these drugs, and new medications with different mechanisms of action are now desperately needed.

A team of Canadian and American researchers has discovered that an enzyme with a crucial role in infection operates differently in one class of bacteria than another —a promising new clue in the search for new antibiotics. The scientists, from the University of Waterloo, the University of Colorado, and Oregon Health and Science University, published their findings in the journal Protein Science.

Using the Canadian Light Source at the University of Saskatchewan, the researchers have for the first time comprehensively imaged a gram-positive HtrA enzyme (high-temperature requirement A) in Streptococcus pneumoniae, the main cause of community acquired pneumonia and meningitis in children and the elderly.

HtrA enzymes are well researched in the class of bacteria known as gram-negative but poorly understood in gram-positive bacteria. Gram‑negative organisms (e.g., E. coli, Pseudomonas) survive well in hospital environments and are major drivers of hospital‑acquired infections and antibiotic‑resistance outbreaks.

Todd Holyoak, an associate professor and associate dean in Waterloo’s Department of Biology was one of the Canadian researchers involved in the project.  He says the team discovered that, in gram-positive bacteria, HtrA enzymes have a dynamic structure.

"It basically transitions between different states ... and sort of oscillates between these states,” Holyoak says. “This oscillation is essential to its function.”

This discovery is significant because existing drugs targeting this enzyme are unlikely to work on gram-positive bacteria, since they are designed to affect an enzyme that does not change shape.

The research points to a promising new angle for antimicrobial research: preventing these enzymes from working can stop gram-positive bacteria from becoming infectious.

“It is a good target” for drug research, Holyoak says. “If we knock out this function, then we can actually have an agent that prevents bacterial infection.”

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Lee, Eunjeong, Jasmina S. Redzic, Blaine Gordon, Anthony J. Saviola, Norman Tran, Sean P. Maroney, Nathanael L. Ashby et al. "Streptococcus pneumoniae HtrA is a dynamic and monomeric virulence factor capable of forming larger oligomeric complexes." Protein Science 35, no. 1 (2026): e70411. https://doi.org/10.1002/pro.70411Digital Object Identifier (DOI)

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