A Deep Learning Approach to Antibiotic Discovery.

Journal: Cell
PMID: 32084340

Abstract

Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover new antibiotics. To address this challenge, we trained a deep neural network capable of predicting molecules with antibacterial activity. We performed predictions on multiple chemical libraries and discovered a molecule from the Drug Repurposing Hub-halicin-that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae. Halicin also effectively treated Clostridioides difficile and pan-resistant Acinetobacter baumannii infections in murine models. Additionally, from a discrete set of 23 empirically tested predictions from >107 million molecules curated from the ZINC15 database, our model identified eight antibacterial compounds that are structurally distant from known antibiotics. This work highlights the utility of deep learning approaches to expand our antibiotic arsenal through the discovery of structurally distinct antibacterial molecules.

Authors

  • Jonathan M Stokes
    Department of Biological Engineering, Synthetic Biology Center, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Machine Learning for Pharmaceutical Discovery and Synthesis Consortium, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Kevin Yang
    Computer Science and Artificial Intelligence Laboratory , MIT , Cambridge , Massachusetts 02139 , United States.
  • Kyle Swanson
  • Wengong Jin
    Computer Science and Artificial Intelligence Laboratory , Massachusetts Institute of Technology , 77 Massachusetts Avenue , Cambridge , MA 02139 , USA . Email: regina@csail.mit.edu.
  • Andres Cubillos-Ruiz
    Department of Biological Engineering, Synthetic Biology Center, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
  • Nina M Donghia
    Department of Biological Engineering, Synthetic Biology Center, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
  • Craig R MacNair
    Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Shawn French
    Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Lindsey A Carfrae
    Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Zohar Bloom-Ackermann
    Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Victoria M Tran
    Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Anush Chiappino-Pepe
    Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Ahmed H Badran
    Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Ian W Andrews
    Department of Biological Engineering, Synthetic Biology Center, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
  • Emma J Chory
    Department of Biological Engineering, Synthetic Biology Center, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • George M Church
    Wyss Institute for Biologically Inspired Engineering , Boston, Massachusetts 02115, United States.
  • Eric D Brown
    Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • Tommi S Jaakkola
    Computer Science and Artificial Intelligence Laboratory , Massachusetts Institute of Technology , 77 Massachusetts Avenue , Cambridge , MA 02139 , USA . Email: regina@csail.mit.edu.
  • Regina Barzilay
    Computer Science and Artificial Intelligence Laboratory , Massachusetts Institute of Technology , 77 Massachusetts Avenue , Cambridge , MA 02139 , USA . Email: regina@csail.mit.edu.
  • James J Collins
    Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

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