Discovery of antibiotics in the archaeome using deep learning Antimicrobial resistance (AMR) is one of the greatest threats facing humanity, making the need for new antibiotics more critical than ever. While most antibiotics have traditionally been derived from bacteria and fungi, archaea—a distinct and underexplored domain of life—offer a largely untapped reservoir for antibiotic discovery. In this study, we leveraged deep learning to systematically explore the archaeome, uncovering promising new candidates for combating AMR. By mining 233 archaeal proteomes, we identified 12,623 molecules with potential antimicrobial activity. These newly discovered peptide compounds, termed archaeasins, exhibit unique compositional features that differentiate them from traditional antimicrobial peptides, including a distinct amino acid profile. We synthesized 80 archaeasins, 93% of which demonstrated antimicrobial activity in vitro . Notably, in vivo validation identified archaeasin-73 as a lead candidate, significantly reducing bacterial loads in mouse infection models, with effectiveness comparable to established antibiotics like polymyxin B. Our findings highlight the immense potential of archaea as a resource for developing next-generation antibiotics. ### Competing Interest Statement CFN provides consulting services to Invaio Sciences and is a member of the Scientific Advisory Boards of Nowture S.L., Peptidus, and Phare Bio. CFN is also on the Advisory Board of the Peptide Drug Hunting Consortium (PDHC). The de la Fuente Lab has received research funding or in-kind donations from United Therapeutics, Strata Manufacturing PJSC, and Procter & Gamble, none of which were used in support of this work. An invention disclosure associated with this work has been filed.

Discovery of antibiotics in the archaeome using deep learning www.biorxiv.org/content/10.1...

Q. @cfuentes @upenn.bsky.social

If #archaeome is for the Archae, then #palaeome is for omics from ancient samples?😀👍

Defensins identified through molecular de-extinction
www.cell.com/cell-reports...