Nature Portfolio

Thrilled to share that our paper, “Deep learning reveals antimicrobial peptides within prions,” is now published in @NatureMicrobiol @NaturePortfolio. In this work, we used AI to ask an unexpected question: could proteins best known for their role in fatal neurodegenerative diseases also encode molecules that fight infection? Prions and prion-like proteins are usually viewed through the lens of misfolding, aggregation, and disease. But biology is often more layered than our labels suggest. Our study shows that these proteins can contain encrypted antimicrobial peptides, which we call prionins. This connection did not come out of nowhere. Previous studies had shown that certain amyloid-associated protein sequences, including amyloid-β and the cellular prion protein, can have antimicrobial or host-protective activity. But until now, this had not been explored systematically across prion and prion-like proteins at scale. Using our deep-learning platform APEX 1.1, we screened 19.3 million peptide fragments from 2,897 prion-related proteins. This search identified 1,179 candidate antimicrobial peptides, moving from scattered observations to a global AI-guided search across millions of possible protein fragments. We then moved from prediction to experiment. Of 75 synthesized prionins, 59 inhibited at least one bacterial pathogen, including multidrug-resistant strains. Forty-two showed activity at 16 µM or lower against at least one pathogen. Many prionins disrupted bacterial membranes, and a subset showed encouraging early selectivity, including minimal hemolysis and limited cytotoxicity. Two lead prionins also reduced Acinetobacter baumannii burden in a mouse skin-infection model, with efficacy comparable to polymyxin B in the model tested. This is still early-stage work. We do not show that prionins are naturally released during infection or that they function physiologically in host defense, and these findings do not represent a treatment ready for patients. But the study raises a provocative idea: proteins long viewed mainly as biological “villains” may also encode useful molecular functions. More broadly, it shows how AI can become a discovery engine for biology: helping us search hidden molecular spaces, connect seemingly distant fields such as neurodegeneration and innate immunity, and uncover new starting points for medicine in places we might never have thought to look. At a time when new antibiotics are urgently needed, expanding where we search matters. Deeply grateful to @mdt_torres, Fangping Wan, and everyone who made this work possible, including @Penn, @CBE_Penn, @PennBioeng, @PennEngAI, @PennEngineers, @PennMedicine, @PennChemistry, @PennMicro, @PennPsych, and @PennSAS. nature.com/articles/s41564-0…