University of Oregon biologists have resurrected prehistoric proteins up to 160 million years old that carry natural antimicrobial properties. The revived molecules could inspire the design of new treatments for antibiotic-resistant infections, a pressing global health issue.
Described in a paper published in PLOS Biology on Aug. 25, the scientists worked their way up the tree of life, reconstructing peptides — short protein fragments — dating back to the earliest placental mammals, the diverse lineage that includes humans and nearly all mammals alive today. In laboratory tests, the researchers found that some of the extinct peptides were more potent against drug-resistant bacteria than some of their present-day counterparts.
Evolution’s ancient remedies could offer new starting points for scientists designing treatments that supplement or replace antibiotics that no longer work , said Matt Barber , senior author of the paper and evolutionary biologist at the UO College of Arts and Sciences .
“For anybody who studies pathogenic bacteria, it’s always in the back of our minds that antibiotics are one of the most important breakthroughs in medicine in the 20th century,” Barber said. “But bacteria are, and have been for a long time, evolving resistance to them.”
He continued: “We’re definitely interested in whether by resurrecting or engineering some enhanced antimicrobial peptides, we could use these as therapeutics down the road.”
Seeking old wisdom from antimicrobial peptides
Some 160 million years ago, near the end of the Jurassic Period, the ancestor of all placental mammals, whose young develop in the womb, emerged — and so did lactoferrin, the protein at the center of Barber’s investigation.
Lactoferrin is an immune protein found in nearly every body fluid except blood: breast milk, tears, saliva, snot, intestinal mucus. Its main function is to withhold iron from pathogens. Bacteria in the body need iron to fuel their advances, but lactoferrin acts as a vault, tightly sealing the key resource away.
In addition to securing iron from bacterial reach, lactoferrin has evolved built-in tools to fight against pathogens. Most notably, it has an antimicrobial peptide that punches holes in the membranes of bacteria, rupturing the cell.
“Antimicrobial peptides are a key part of the body’s first line of defense,” said Titas Sil, lead author of the paper and a doctoral student in Barber’s lab. “They can target a broad range of pathogens, and due to their potency, scientists have been trying to synthesize a variety for therapeutic uses.”
None of lactoferrin’s close protein relatives have that bacteria-killing ability, suggesting that the property arose sometime after lactoferrin emerged in the mammalian lineage. To find out when and how it has evolved since, the researchers worked backward through its evolutionary history and resurrected its ancestors.
A look at the past might give ideas for a healthier future, Barber said.
“Evolution is essentially a billions-year-old science experiment, right?” he said.
“We’re seeing the results of what worked and what didn’t work. Looking at how traits are naturally produced and selected through evolution, you can get information that could be useful for designing new antimicrobial tools.”
Opening doors for drug discovery and innovation
To resurrect the extinct antimicrobial peptide, Sil first compared the gene sequences of lactoferrin in present-day organisms like humans and cows. Mapping their evolutionary relationships, she statistically inferred the most likely sequences of their common ancestors, reaching back about 160 million years.
That state-of-the-art technique is known as ancestral sequence reconstruction, which was pioneered by Joseph Thornton , a former UO scientist whose previous lab space is now home to Barber’s group.
After synthesizing the predicted gene and regenerating the ancient protein in cells, Sil then tested their potency against several pathogens associated with human diseases, including Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Streptococcus. The earliest resurrected antimicrobial peptides disturbed the bacterial membranes, but the pathogens were somehow able to repair the damage and tolerate the peptide. But peptides of later mammalian ancestors, about a few million years old, displayed progressively stronger antimicrobial activity, sometimes outperforming the modern, human versions.
That difference came down to a small structural change: a single mutation in the amino acid chain, the protein “building blocks,” that made the antimicrobial peptide more potent.
“What was surprising and unexpected was how small changes in these domains could have such large effects,” Barber said. “There have been clinical trials using derivatives of human lactoferrin peptides to treat infections. But there were several instances where (Sil) showed that you don’t need a lot of changes for evolution to enhance the activity of these peptides beyond the human versions.”
But Barber and Sil caution that the development of new drugs with extinct antimicrobial peptides is unlikely to be immediate. Compared to conventional antibiotics, the peptides are structurally less stable and quickly broken down in the body.
Still, tracing their history matters, Barber said. Understanding how antimicrobial peptides evolved in the past is one of the best ways to inspire new treatment designs that pathogens can’t attack.
“Similar to antibiotics, pathogens are going to be able to evolve against antimicrobial peptides,” he said. “But if we understand and can anticipate how they become resistant to these molecules, we can hopefully find better ways to target them or develop combination treatments that better avoid resistance.”
— By Leila Okahata, University Communications
This research was funded by the National Institutes of Health.
About the University of Oregon College of Arts and Sciences
The University of Oregon College of Arts and Sciences supports the UO’s mission and shapes its identity as a comprehensive research university. With disciplines in the humanities and social and natural sciences, the College of Arts and Sciences serves approximately two-thirds of all UO students. The College of Arts and Sciences faculty includes some of the world’s most accomplished researchers, and the more than $75 million in sponsored research activity of the faculty underpins the UO’s status as a Carnegie Research I institution and its membership in the Association of American Universities.
PLOS Biology
Retracing the origin and evolution of a cryptic antimicrobial 2 peptide within mammalian lactoferrin
25-Aug-2026