Biologists at the University of Oregon have reached deep into evolutionary history to resurrect prehistoric proteins that may hold promise against modern drug‑resistant bacteria. Their findings, published in PLOS Biology under the title “Retracing the origin and evolution of a cryptic antimicrobial peptide within mammalian lactoferrin”, reveal that peptides dating back 160 million years carried natural antimicrobial properties, in some cases more potent than those found in humans today. Senior author Matt Barber, PhD, an evolutionary biologist at the UO College of Arts and Sciences, led the study.
The research focused on lactoferrin, an iron‑binding immune protein found in breast milk, saliva, tears, and mucus. Lactoferrin not only sequesters iron to starve pathogens but also contains an embedded antimicrobial peptide (AMP) called lactoferricin, which ruptures bacterial membranes. To trace its origins, Barber’s team used ancestral sequence reconstruction (ASR), a state‑of‑the‑art technique that infers ancient gene sequences by comparing modern relatives. Doctoral student Titas Sil, the paper’s first author, synthesized these ancestral peptides and tested them against pathogens including Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.
The results were striking. Even the earliest reconstructed peptides showed membrane‑permeabilizing activity, though pathogens could sometimes repair the damage. Later ancestral peptides, however, displayed progressively stronger antimicrobial effects, in some cases outperforming modern human lactoferricin. A single amino acid mutation was enough to dramatically enhance potency. “What was surprising and unexpected was how small changes in these domains could have such large effects,” Barber noted.
While clinical application is not immediate — peptides are structurally less stable than conventional antibiotics and degrade quickly in the body — the study demonstrates how evolution’s ancient experiments can inform modern drug design. By understanding how antimicrobial peptides evolved and how pathogens adapted to them, scientists may anticipate resistance and engineer more durable therapies.
For peptide science, the work underscores the potential of ancestral peptides as templates for next‑generation antimicrobials. As Barber put it, “Evolution is essentially a billions‑year‑old science experiment. Looking at how traits are naturally produced and selected, you can get information that could be useful for designing new antimicrobial tools.”