PHILADELPHIA – New antibiotic candidates for drug-resistant bacteria may reside inside prions, mis-folded protein in the brain best known for rare and fatal degenerative brain diseases. Prion and prion-like proteins may hide short peptides, named "prionins," that can kill bacteria, suggesting proteins best known for their role in neurodegeneration may contain molecular features linked to immune defense, according to new research from the Perelman School of Medicine at the University of Pennsylvania.
From fatal brain disease to antibiotic discovery
The findings, published today in Nature Microbiology , point to a surprising new place to search for antibiotic candidates at a time when drug-resistant infections are narrowing treatment options. The work also raises a broader biological question: whether proteins most often associated with neurodegeneration may contain hidden molecular features connected to innate immunity.
Earlier studies had hinted at this link. Researchers had reported that fragments from some proteins, including amyloid-beta, which is involved in neurodegenerative diseases like Alzheimer's disease, and the cellular prion protein, including amyloid-beta and the cellular prion protein, could fight microbes. But no one had systematically searched prion and prion-like proteins at scale for hidden antimicrobial peptides. The Penn team used AI to do that.
AI search reveals a hidden class of antimicrobial peptides
The Penn team used a deep-learning platform called APEX 1.1 to scan 19.3 million short peptide fragments from 2,897 prion and prion-like proteins. APEX can predict the antibiotic activity of a given amino acid sequence, identifying 1,179 candidate antimicrobial peptides. The researchers named the new class "prionins."
"This work changes where we think antibiotics might be hiding," said César de la Fuente , PhD, FRSB, Presidential Associate Professor and director of the Machine Biology Group at the University of Pennsylvania Perelman School of Medicine and senior author of the study. "Prions have long been seen almost entirely through the lens of disease, but AI let us ask a different question: whether these proteins also encode useful molecular fragments. The answer appears to be yes."
Lab and mouse tests validate promising candidates
The study team selected 75 of the most promising peptides for experimental testing based on how well the platform assessed they would perform against 11 different bacterial pathogens, including drug-resistant strains. Of those, 59 inhibited at least one bacterial pathogen, and 42 showed strong activity at low concentrations, a designation especially important for.
Additional experiments suggested that many of the active prionins work by disrupting bacterial membranes, a common strategy used by antimicrobial peptides. Signs of toxicity were limited, and 16 active peptides showed no measurable harm to red blood cells or human cells at the highest concentrations tested.
To verify these findings, researchers tested two of the most promising peptides—one from a fungus and one from a roundworm—in mice. They found that the approach reduced bacteria levels in a standard skin infection model caused by Acinetobacter baumannii, a difficult-to-treat pathogen. Their effects were comparable to polymyxin B, and researchers saw no treatment-related weight loss.
"This is where the story becomes more than a computer screen," said Marcelo D. T. Torres, co-first author of the study. "The AI search gave us a short list of candidates, but the important point is that many of those molecules worked in the lab, and two worked in an animal infection model. That is what makes this a discovery platform, not just a prediction exercise."
A new frontier in antibiotic discovery
The findings build on the de la Fuente Lab's broader effort to mine the biological world for "encrypted peptides" - short, hidden sequences inside larger proteins that can have biological functions when isolated. Previous work from the group has searched human proteins, extinct organisms, archaea, microbiomes, and venoms. The prion study expands that idea into one of biology's most unexpected protein classes.
The study also raises an intriguing possibility at the intersection of neurodegeneration and innate immunity. It does not show that prionins are naturally released during infection or that prion and prion-like proteins normally act as antibiotics in the body. It also does not change what is known about the harmful role of misfolded prions in neurodegenerative disease. Instead, the work suggests that these proteins may be a rich and previously overlooked source of antibiotic candidates, and a new place to ask questions about links between protein aggregation and host defense.
"For a long time, drug discovery has been limited not only by what we can test, but by where we choose to look," de la Fuente said. "AI is changing that. It gives us a way to search the hidden layers of biology and ask whether molecules associated with one story - in this case, disease - may also carry another story with therapeutic potential."
