Researchers have discovered how an enzyme produced by immune system cells carries out a deadly, multipronged attack on invading bacteria. The enzyme, granzyme B, is released by cytotoxic T cells as part of the body’s natural fight against intracellular microbes. Collaborators at the University of Michigan and at Harvard University have now found that, unlike antibiotics, which disrupt a single bacterial process, granzyme B impacts on multiple bacterial processes all at the same time. The findings could potentially help scientists develop new antibiotics that are effective against existing multidrug-resistant pathogens and that prevent bacteria from developing resistance. Understanding how the enzyme exerts its multifaceted attack could also suggest how combinations of existing drugs might be repurposed to fight infection.
“We have a huge crisis of antibiotic resistance right now in that most drugs that treat diseases like tuberculosis or listeria, or pathogens like E. coli, are not effective,” stated Sriram Chandrasekaran, Ph.D., University of Michigan professor of biomedical engineering. “So there is a huge need for figuring out how the immune system does its work. We hope to design a drug that goes after bacteria in a similar way.” The researchers report their findings in Cell, in a paper entitled “Granzyme B Disrupts Central Metabolism and Protein Synthesis in Bacteria to Promote an Immune Cell Death Program.”
Working with Harvard’s Judy Lieberman, M.D., Ph.D., Dr. Chandrasekaran’s team used a differential proteomics approach to identify granzyme B substrates in three unrelated bacteria, Escherichia coli, Listeria monocytogenes, and Mycobacteria tuberculosis. They found that in all three bacteria the enzyme targets a highly conserved set of proteins, which are involved in biosynthetic and metabolic pathways that are critical for bacterial cell survival under different environmental conditions. Other key protein targets of the enzyme included those required for protein synthesis, folding, and degradation, which are processes that man-made antibiotics also target.
“When exposed to granzyme B, the bacteria were unable to develop resistance to the multipronged attack, even after exposure over multiple generations,” Chandrasekaran said. “This enzyme breaks down multiple proteins that are essential for the bacteria to survive. It's essentially killing several birds with one stone.”
The researchers are now investigating mechanisms that bacteria use to avoid T-cell attack. “We’ve reached a point where we take what antibiotics can do for granted, and we can’t do that anymore,” Chandrasekaran stated. “We’re taking inspiration from the human immune system, which has been fighting infections for many thousands of years.”