Ancient mammalian antimicrobial peptides revealed stronger bacteria-killing activity in some cases, offering clues for designing future treatments against resistant infections.
Some proteins that vanished millions of years ago may still have something to teach scientists about fighting modern infections. University of Oregon biologists have reconstructed antimicrobial molecules dating back as far as 160 million years, and laboratory tests showed that some ancient versions were more effective against drug-resistant bacteria than their modern counterparts.
The work, described in a paper published in PLOS Biology on Aug. 25, traced these peptides — short protein fragments — through the evolutionary history of placental mammals, the lineage that includes humans and nearly all mammals living today.
For Matt Barber, senior author of the paper and an evolutionary biologist at the UO College of Arts and Sciences, those ancient molecules could provide starting points for treatments that complement or replace antibiotics that no longer work.
“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.”
Lactoferrin evolved a bacteria-killing defense
Near the end of the Jurassic Period, about 160 million years ago, the ancestor shared by all placental mammals, whose young develop in the womb, appeared. Around the same time, lactoferrin, the immune protein at the center of Barber’s research, also emerged.
Lactoferrin occurs in nearly every bodily fluid except blood, including breast milk, tears, saliva, snot, and intestinal mucus. One of its primary defenses against pathogens is withholding iron. Bacteria need iron to grow and spread, and lactoferrin binds the resource tightly enough to keep it out of their reach.
But lactoferrin also carries another defensive weapon. An antimicrobial peptide embedded within the protein can puncture bacterial membranes and rupture the cells.
“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.”
Lactoferrin’s closest protein relatives lack this bacteria-killing ability, indicating that the trait developed sometime after lactoferrin appeared in the mammalian lineage. To determine when it arose and how it changed afterward, the researchers retraced the protein’s evolutionary history and reconstructed its ancestral forms.
Barber said looking backward through evolution could provide ideas for improving future treatments.
“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.”
Ancient proteins revealed stronger defenses
Sil began by comparing lactoferrin gene sequences from living species such as humans and cows. Using their evolutionary relationships, she statistically reconstructed the most likely sequences carried by their common ancestors, reaching approximately 160 million years into the past.
The method, called ancestral sequence reconstruction, which was pioneered by Joseph Thornton, a former UO scientist whose previous lab space is now home to Barber’s group, allowed the researchers to recreate proteins that no longer exist in living organisms.
After synthesizing the predicted genes and producing the ancient proteins in cells, Sil tested their antimicrobial activity against pathogens associated with human disease, including Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Streptococcus.
The oldest reconstructed peptides damaged bacterial membranes, but the bacteria somehow repaired that damage and tolerated the attack. Peptides reconstructed from later mammalian ancestors, including versions only a few million years old, showed progressively greater antimicrobial activity. Some even surpassed the modern human versions.
One mutation sharply increased potency
The stronger activity could be traced to a remarkably small structural difference: a single mutation in the chain of amino acids, the protein “building blocks,” increased the peptide’s potency.
“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.”
Drug development still faces major hurdles
Barber and Sil caution that resurrecting ancient antimicrobial peptides does not mean new drugs are imminent. Compared with conventional antibiotics, these peptides are less structurally stable and are broken down rapidly inside the body.
Even so, Barber argues that reconstructing their evolutionary history could help scientists understand how antimicrobial activity changes and provide ideas for treatments designed to remain useful as pathogens evolve.
“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.”
Reference: “Retracing the origin and evolution of a cryptic antimicrobial peptide within mammalian lactoferrin” by Titas Sil, Caitlin H. Kowalski, Sierra Scamfer, Natalie Copeland and Matthew F. Barber, 25 August 2026, PLOS Biology.
DOI: 10.1371/journal.pbio.3003932
This research was funded by the National Institutes of Health.
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