Scientists resurrect 160-million-year-old proteins to combat antibiotic resistance

In a laboratory at the University of Oregon, scientists have brought back to life proteins that last existed 160 million years ago—ancient molecular defenses that once protected the earliest placental mammals from infection. What they found in these resurrected molecules is striking: some of the prehistoric versions work better against modern drug-resistant bacteria than the versions we carry in our bodies today.

The work, published in PLOS Biology in late August, centers on lactoferrin, an immune protein that appears in nearly every body fluid except blood—breast milk, tears, saliva, mucus. Its primary job is straightforward: it starves bacteria by locking away iron, an element pathogens need to survive. But lactoferrin also carries something more aggressive: an antimicrobial peptide, a short protein fragment that punctures bacterial cell membranes and ruptures them from the inside. The question the Oregon team asked was simple but profound: how did this killing ability evolve, and what can we learn from its history?

To answer it, lead researcher Titas Sil compared the genetic sequences of lactoferrin across living species—humans, cows, and others—and worked backward through evolutionary time. Using a technique called ancestral sequence reconstruction, she statistically inferred what the gene sequences of common ancestors must have looked like, reaching back roughly 160 million years to the origin of placental mammals. She then synthesized those predicted genes and regenerated the ancient proteins in laboratory cells. The result was a collection of extinct antimicrobial peptides spanning millions of years of evolutionary history.

When tested against four bacterial pathogens known to cause human disease—Pseudomonas aeruginosa, Staphylococcus aureus, E. coli, and Streptococcus—the ancient peptides behaved differently depending on their age. The oldest versions could damage bacterial membranes but the bacteria managed to repair the injury and survive. However, peptides from later mammalian ancestors, only a few million years old, showed progressively stronger antimicrobial activity. Some of these intermediate versions actually outperformed the modern human peptide. The difference was tiny: a single mutation in the amino acid chain, the building blocks of proteins, had made the ancient versions more lethal to bacteria.

Matt Barber, the senior author and an evolutionary biologist at the university, frames this discovery as a window into nature's long experiment. "Evolution is essentially a science experiment billions of years old," he said. "We're seeing the results of what worked and what didn't work." The implication is clear: if we understand how evolution optimized these antimicrobial tools over millions of years, we might be able to design better ones ourselves. The timing matters. Antibiotic resistance is now a global health crisis. Bacteria have been evolving defenses against our drugs for decades, and the arsenal of effective antibiotics is shrinking. New approaches are urgent.

But the researchers are careful not to oversell what they have found. Antimicrobial peptides are structurally fragile compared to conventional antibiotics. They break down quickly in the body, making them difficult to use as drugs. Clinical trials using derivatives of human lactoferrin peptides have already been attempted, with mixed results. Barber and Sil acknowledge that turning these ancient molecules into actual medicines will take years, if it happens at all. Yet the deeper insight may matter more than any single drug. If scientists can understand how pathogens evolve resistance to these peptides, they might be able to anticipate that resistance and design combination treatments that bacteria cannot easily overcome. The ancient proteins, in other words, are not the answer. But the story of how they changed over time might be.