A generative deep learning approach to de novo antibiotic design

Aarti Krishnan¹, Melis N Anahtar², Jacqueline A Valeri³, Wengong Jin⁴, Nina M Donghia⁵, Leif Sieben⁶, Andreas Luttens⁷, Yu Zhang³, Seyed Majed Modaresi³, Andrew Hennes⁸, Jenna Fromer⁹, Parijat Bandyopadhyay⁷, Jonathan C Chen⁷, Danyal Rehman¹⁰, Ronak Desai¹¹, Paige Edwards⁷, Ryan S Lach¹², Marie-Stéphanie Aschtgen¹³, Margaux Gaborieau¹³, Massimiliano Gaetani¹⁴, Samantha G Palace¹⁵, Satotaka Omori¹², Lutete Khonde¹⁶, Yurii S Moroz¹⁷, Bruce Blough¹⁸, Chunyang Jin¹⁸, Edmund Loh¹⁹, Yonatan H Grad¹⁵, Amir Ata Saei¹³, Connor W Coley²⁰, Felix Wong²¹, James J Collins²²

Affiliations

¹ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
² Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Departments of Pathology and Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
³ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
⁴ Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Khoury College of Computer Sciences, Northeastern University, Boston, MA 02115, USA.
⁵ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
⁶ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland.
⁷ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁸ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
⁹ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁰ Mila-Quebec AI Institute, Montréal, QC H2S 3H1, Canada.
¹¹ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard Medical School, Boston, MA 02115, USA.
¹² Integrated Biosciences, Inc., Redwood City, CA 94065, USA.
¹³ Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
¹⁴ Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17 177 Stockholm, Sweden; Chemical Proteomics Unit, Science for Life Laboratory (SciLifeLab), 171 77Stockholm, Sweden.
¹⁵ Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
¹⁶ Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁷ Enamine Ltd., 67 Winston Churchill Street, Kyiv 02094, Ukraine; Chemspace LLC, 85 Winston Churchill Street, Kyiv 02094, Ukraine; Department of Chemistry, Taras Shevchenko National University of Kyiv, 60 Volodymyrska Street, Kyiv 01601, Ukraine.
¹⁸ Center for Drug Discovery, RTI International, Research Triangle Park, Durham, NC 27713, USA.
¹⁹ Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; Clinical Microbiology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
²⁰ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
²¹ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Integrated Biosciences, Inc., Redwood City, CA 94065, USA.
²² Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA. Electronic address: jimjc@mit.edu.

PMID: 40816267
DOI: 10.1016/j.cell.2025.07.033

A generative deep learning approach to de novo antibiotic design

Aarti Krishnan et al. Cell. 2025.

. 2025 Aug 7:S0092-8674(25)00855-4.

doi: 10.1016/j.cell.2025.07.033. Online ahead of print.

Authors

Affiliations

¹ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
² Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Departments of Pathology and Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
³ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
⁴ Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Khoury College of Computer Sciences, Northeastern University, Boston, MA 02115, USA.
⁵ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
⁶ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland.
⁷ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁸ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
⁹ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁰ Mila-Quebec AI Institute, Montréal, QC H2S 3H1, Canada.
¹¹ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard Medical School, Boston, MA 02115, USA.
¹² Integrated Biosciences, Inc., Redwood City, CA 94065, USA.
¹³ Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
¹⁴ Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17 177 Stockholm, Sweden; Chemical Proteomics Unit, Science for Life Laboratory (SciLifeLab), 171 77Stockholm, Sweden.
¹⁵ Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
¹⁶ Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁷ Enamine Ltd., 67 Winston Churchill Street, Kyiv 02094, Ukraine; Chemspace LLC, 85 Winston Churchill Street, Kyiv 02094, Ukraine; Department of Chemistry, Taras Shevchenko National University of Kyiv, 60 Volodymyrska Street, Kyiv 01601, Ukraine.
¹⁸ Center for Drug Discovery, RTI International, Research Triangle Park, Durham, NC 27713, USA.
¹⁹ Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; Clinical Microbiology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
²⁰ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
²¹ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Integrated Biosciences, Inc., Redwood City, CA 94065, USA.
²² Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA. Electronic address: jimjc@mit.edu.

PMID: 40816267
DOI: 10.1016/j.cell.2025.07.033

Abstract

The antimicrobial resistance crisis necessitates structurally distinct antibiotics. While deep learning approaches can identify antibacterial compounds from existing libraries, structural novelty remains limited. Here, we developed a generative artificial intelligence framework for designing de novo antibiotics through two approaches: a fragment-based method to comprehensively screen >10⁷ chemical fragments in silico against Neisseria gonorrhoeae or Staphylococcus aureus, subsequently expanding promising fragments, and an unconstrained de novo compound generation, each using genetic algorithms and variational autoencoders. Of 24 synthesized compounds, seven demonstrated selective antibacterial activity. Two lead compounds exhibited bactericidal efficacy against multidrug-resistant isolates with distinct mechanisms of action and reduced bacterial burden in vivo in mouse models of N. gonorrhoeae vaginal infection and methicillin-resistant S. aureus skin infection. We further validated structural analogs for both compound classes as antibacterial. Our approach enables the generative deep-learning-guided design of de novo antibiotics, providing a platform for mapping uncharted regions of chemical space.

Keywords: Neisseria gonorrhoeae; Staphylococcus aureus; antibiotics; bacterial infection; de novo design; drug discovery; fragments; generative artificial intelligence; graph neural networks; machine learning.

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Conflict of interest statement

Declaration of interests J.J.C. is an academic co-founder and Scientific Advisory Board chair of Phare Bio, a non-profit venture focused on antibiotic drug development, an academic co-founder and board member of Cellarity, and the founding Scientific Advisory Board chair of Integrated Biosciences. M.N.A. is a co-founder and consultant to Day Zero Diagnostics. F.W. is a co-founder of Integrated Biosciences. R.S.L. and S.O. have equity interests in Integrated Biosciences. Y.S.M. is an employee of Enamine Ltd. and a scientific advisor of Chemspace LLC.

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A generative deep learning approach to de novo antibiotic design

Affiliations

A generative deep learning approach to de novo antibiotic design

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

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Medical