Molecular de-extinction of antibiotics enabled by deep learning

Molecular de-extinction is an emerging field that aims to resurrect molecules to solve present-day problems such as antibiotic resistance. Here, we introduce a deep learning approach called Antibiotic Peptide de-Extinction (APEX) to mine the proteomes of all available extinct organisms (the “extinctome”) searching for encrypted peptide (EP) antibiotics. APEX mined a total of 10,311,899 EPs and identified 37,176 sequences predicted to have broad-spectrum antimicrobial activity, 11,035 of which were not found in extant organisms. Chemical synthesis and experimental validation yielded archaic EPs (AEPs) with activity against dangerous bacterial pathogens. Most peptides killed bacteria by depolarizing their cytoplasmic membrane, contrary to known antimicrobial peptides, which target the outer membrane. Notably, lead peptides, including those derived from the woolly mammoth, ancient sea cow, giant sloth, and extinct giant elk, exhibited anti-infective activity in preclinical mouse models. We propose molecular de-extinction, accelerated by deep learning, as a framework for discovering therapeutic molecules. ### Competing Interest Statement Cesar de la Fuente-Nunez provides consulting services to Invaio Sciences and is a member of the Scientific Advisory Boards of Nowture S.L. and Phare Bio. 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.