Fangping Wan, Marcelo D. T. Torres, Jacqueline Peng, Cesar de la Fuente-Nunez
{"title":"Deep-learning-enabled antibiotic discovery through molecular de-extinction","authors":"Fangping Wan, Marcelo D. T. Torres, Jacqueline Peng, Cesar de la Fuente-Nunez","doi":"10.1038/s41551-024-01201-x","DOIUrl":null,"url":null,"abstract":"Molecular de-extinction aims at resurrecting molecules to solve antibiotic resistance and other present-day biological and biomedical problems. Here we show that deep learning can be used to mine the proteomes of all available extinct organisms for the discovery of antibiotic peptides. We trained ensembles of deep-learning models consisting of a peptide-sequence encoder coupled with neural networks for the prediction of antimicrobial activity and used it to mine 10,311,899 peptides. The models predicted 37,176 sequences with broad-spectrum antimicrobial activity, 11,035 of which were not found in extant organisms. We synthesized 69 peptides and experimentally confirmed their activity against bacterial pathogens. Most peptides killed bacteria by depolarizing their cytoplasmic membrane, contrary to known antimicrobial peptides, which tend to target the outer membrane. Notably, lead compounds (including mammuthusin-2 from the woolly mammoth, elephasin-2 from the straight-tusked elephant, hydrodamin-1 from the ancient sea cow, mylodonin-2 from the giant sloth and megalocerin-1 from the extinct giant elk) showed anti-infective activity in mice with skin abscess or thigh infections. Molecular de-extinction aided by deep learning may accelerate the discovery of therapeutic molecules. Deep learning can be used to mine the proteomes of all available extinct organisms for the discovery of compounds with antibiotic properties.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 7","pages":"854-871"},"PeriodicalIF":26.8000,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01201-x.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Biomedical Engineering","FirstCategoryId":"5","ListUrlMain":"https://www.nature.com/articles/s41551-024-01201-x","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, BIOMEDICAL","Score":null,"Total":0}
引用次数: 0
Abstract
Molecular de-extinction aims at resurrecting molecules to solve antibiotic resistance and other present-day biological and biomedical problems. Here we show that deep learning can be used to mine the proteomes of all available extinct organisms for the discovery of antibiotic peptides. We trained ensembles of deep-learning models consisting of a peptide-sequence encoder coupled with neural networks for the prediction of antimicrobial activity and used it to mine 10,311,899 peptides. The models predicted 37,176 sequences with broad-spectrum antimicrobial activity, 11,035 of which were not found in extant organisms. We synthesized 69 peptides and experimentally confirmed their activity against bacterial pathogens. Most peptides killed bacteria by depolarizing their cytoplasmic membrane, contrary to known antimicrobial peptides, which tend to target the outer membrane. Notably, lead compounds (including mammuthusin-2 from the woolly mammoth, elephasin-2 from the straight-tusked elephant, hydrodamin-1 from the ancient sea cow, mylodonin-2 from the giant sloth and megalocerin-1 from the extinct giant elk) showed anti-infective activity in mice with skin abscess or thigh infections. Molecular de-extinction aided by deep learning may accelerate the discovery of therapeutic molecules. Deep learning can be used to mine the proteomes of all available extinct organisms for the discovery of compounds with antibiotic properties.
期刊介绍:
Nature Biomedical Engineering is an online-only monthly journal that was launched in January 2017. It aims to publish original research, reviews, and commentary focusing on applied biomedicine and health technology. The journal targets a diverse audience, including life scientists who are involved in developing experimental or computational systems and methods to enhance our understanding of human physiology. It also covers biomedical researchers and engineers who are engaged in designing or optimizing therapies, assays, devices, or procedures for diagnosing or treating diseases. Additionally, clinicians, who make use of research outputs to evaluate patient health or administer therapy in various clinical settings and healthcare contexts, are also part of the target audience.