160-Million-Year-Old Molecules Fight Superbugs Better Than Modern Ones

University of Oregon biologists have reconstructed antimicrobial peptides — short protein fragments that kill bacteria — dating back as far as 160 million years, and found that some ancient versions fought drug-resistant bacteria more effectively than their modern human counterparts. The work, published in the journal PLOS Biology, traced the peptides through the evolutionary history of placental mammals, the lineage that includes humans and nearly all mammals alive today.

The peptides sit inside lactoferrin, an immune protein found in nearly every bodily fluid except blood, including breast milk, tears and saliva. Lactoferrin defends against infection mainly by withholding iron that bacteria need to grow, but it also carries an embedded antimicrobial peptide that can puncture bacterial membranes and rupture the cells. Lactoferrin's closest protein relatives lack this bacteria-killing ability, so the trait developed after lactoferrin itself emerged, about 160 million years ago — around the same time as the common ancestor of all mammals whose young develop in the womb.

To trace when the ability arose, lead author Titas Sil and senior author Matt Barber at the University of Oregon compared lactoferrin gene sequences from living species such as humans and cows, then statistically reconstructed the likely ancestral sequences using a method called ancestral sequence reconstruction. Researchers synthesized the predicted ancient genes, produced the proteins in cells, and tested them against pathogens including Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli and Streptococcus.

The oldest reconstructed peptides damaged bacterial membranes, but the bacteria managed to repair the damage and survive. Peptides from more recent mammalian ancestors showed progressively stronger antimicrobial activity, and some even surpassed the modern human version — a difference traced to a single mutation in the peptide's amino acid chain. "What was surprising and unexpected was how small changes in these domains could have such large effects," Barber said.

Barber and Sil caution that the discovery does not mean new drugs are imminent: compared with conventional antibiotics, these peptides are less structurally stable and break down rapidly inside the body. Clinical trials have already tested derivatives of human lactoferrin peptides against infections.