AI discovers hidden antibiotic candidates inside disease-causing prions

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.

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.

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."