An ancient peptide outperformed modern human lactoferricin against S. aureus—in the lab

Rebuilding a peptide from evolutionary clues

The University of Oregon team inferred ancestral lactoferrin sequences from living mammalian relatives, then synthesized the 25-amino-acid antimicrobial segment lactoferricin for testing. The work did not extract proteins from fossils: lactoferrin arose after a gene duplication in early placental mammals roughly 160 million years ago, and the ancient sequences were statistically reconstructed. journals +1

The reconstructed AncLFcin2 peptide reduced viable Staphylococcus aureus JE2 by about 100,000-fold over 24 hours at 800 micrograms per milliliter. Against Pseudomonas aeruginosa PAO1, 100 micrograms per milliliter produced a 1,000-fold reduction. In those tests, this ancestor also outperformed modern human lactoferricin against S. aureus; bovine lactoferricin remained the strongest variant overall. journals

These were three-replicate lab assays in low-nutrient broth, not infections in animals or people. Researchers also tested E. coli and S. agalactiae, and peptide responses varied by species. journals

One substitution changed the result

Researchers traced some activity to one position: replacing glutamine with arginine at residue 8 was necessary and sufficient to increase the ancestral peptide's activity against P. aeruginosa. But that swap alone did not boost its effect on S. aureus. A separate Q5R change enhanced the human peptide's activity against S. aureus, underscoring how a small sequence change can help against one bacterium without producing a universal antibiotic. journals

Importantly, the team tested short synthetic peptides, not an intact extinct lactoferrin. The paper reports that some weakly active ancestral peptides appeared to promote bacterial growth at low concentrations; the researchers said the cause was uncertain. journals

Why a promising sequence is not a medicine

The need is real: WHO's 2025 surveillance report estimated that about one in six laboratory-confirmed bacterial infections causing common infections in 2023 was resistant to antibiotics. Resistance rose in more than 40% of the pathogen–drug combinations WHO tracked between 2018 and 2023. WHO also describes a thin antimicrobial-drug pipeline. who +1

Yet antimicrobial peptides have been hard to translate into treatments. Nature's reporting on the field describes narrow dose windows, possible toxicity to human tissue and instability in the body as persistent hurdles. nature The Oregon study's low-nutrient broth only approximates host conditions; the researchers say activity trends also appeared in some alternative media, but the work did not establish safety, exposure in the body or efficacy in an infection. journals

The next step is engineering and testing variants under more realistic biological conditions. Until those experiments show that activity survives while toxicity and degradation are controlled, the ancient sequence is a clue for drug design—not an antibiotic ready for patients. journals +1