A new family of antimicrobial peptides called actifensins, produced by mouth bacteria, has been found in dental plaque spanning from Neanderthals to modern humans — maintaining antimicrobial activity across 100,000 years of evolution.
100,000 years of conservationActifensins — antimicrobial peptides produced by oral Actinomyces bacteria — have maintained their structure and antimicrobial function across 100,000 years of evolution, from Neanderthals to modern humans.
What the researchers found
Using a newly developed computational platform called AMPcombi, combined with metagenomics, structural modeling, and experimental validation, the researchers identified actifensins — a novel family of Actinomyces-derived defensin-like antimicrobial peptides — in dental biofilms spanning 100,000 years.
Actifensins were found across all time periods and in samples from humans, Neanderthals, and nonhuman primates, indicating remarkable evolutionary conservation. Phylogenetic and structural analyses revealed shared ancestry between ancient (paleo-) and modern actifensins, with evidence of positive selection driving adaptive diversification.
Critically, experimental validation confirmed that both ancient and modern actifensins maintained antimicrobial activity, demonstrating that these peptides have been functional weapons in microbial competition for at least 100,000 years.
Why it matters
With antibiotic resistance threatening modern medicine, finding new antimicrobial compounds is urgent. This study reveals that ancient dental plaque preserves a 100,000-year evolutionary record of antimicrobial peptides that are still functional. This evolutionary perspective could identify peptides that have been 'battle-tested' by natural selection for millennia, potentially yielding more robust antibiotic candidates than lab-designed molecules. The approach also opens a new field: paleobiotechnology — mining ancient biomolecules for modern drug development.
How the study worked
The team combined multiple approaches: metagenomics analysis of ancient and modern dental calculus samples from humans, Neanderthals, and nonhuman primates; structural modeling to predict peptide structures; their newly developed AMPcombi platform to identify and compare antimicrobial peptides across samples; phylogenetic analysis to trace evolutionary relationships; and experimental antimicrobial assays to validate that identified peptides retained killing activity. The dental calculus samples spanned approximately 100,000 years.
What this study cannot tell us
While actifensins demonstrated antimicrobial activity, the study does not report against which specific pathogens or at what concentrations. Ancient DNA analysis is subject to contamination and degradation challenges. The reconstructed ancient peptide sequences may not perfectly match the original molecules. The AMPcombi platform is newly developed and has not been independently validated by other groups. Translation from evolutionary discovery to therapeutic development remains a long path.
How to read the evidence
This is an innovative interdisciplinary study published in the prestigious Journal of the American Chemical Society, combining metagenomics, structural biology, and experimental validation. The evidence for actifensin identification and evolutionary conservation is strong, though the antimicrobial activity data is preliminary and translational potential remains to be established.
When this study was published
Published in 2025, this is a very recent and groundbreaking study that opens a new frontier in antimicrobial peptide discovery from ancient biological samples.
The bigger picture
The search for new antibiotics has increasingly turned to natural sources — soil bacteria, marine organisms, and now ancient dental plaque. This study represents the emergence of 'evolutionary antimicrobial discovery,' where millions of years of natural selection serve as the screening process. The oral microbiome, preserved in dental calculus, provides an unprecedented window into how antimicrobial peptides have evolved in response to changing microbial communities, potentially revealing design principles that modern drug developers can exploit.
Questions still open
- Could actifensins be effective against modern antibiotic-resistant bacteria like MRSA or drug-resistant gonorrhea?
- What other ancient antimicrobial peptides might be preserved in archaeological dental calculus that haven't been discovered yet?
- Did the shift from hunter-gatherer to agricultural diets change the evolutionary trajectory of oral antimicrobial peptides?
Common questions
How can dental plaque from 100,000 years ago still contain usable antimicrobial peptides?
Could ancient peptides really become modern antibiotics?
Read the original research
Actifensin Evolution in the Human Oral Cavity over the Past 100,000 Years.
Journal of the American Chemical Society, 147(52), 48060-48071
Citation
Herbst, Rosa; Ibrahim, Anan; Hübner, Alexander; Knüpfer, Uwe; Regestein, Lars; Wiedemann, Christoph; Hellmich, Ute A; Warinner, Christina; Stallforth, Pierre. (2025). Actifensin Evolution in the Human Oral Cavity over the Past 100,000 Years.. Journal of the American Chemical Society, 147(52), 48060-48071. https://doi.org/10.1021/jacs.5c14335